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Th~s report contains the colleciive views of on international group o i experts and

does noi necessarily represent the decisions or the stated policy oi the World Health Organizaiion
WHO EXPERT COMMITTEE
ON BIOLOGICAL
STANDARDIZATION
Forty-second Report
Geneva 1992
WHO Library Cataiogu~ng in Publication Data
WHO Expert Committee on Biological Standardization
WHO Expert Committee on Biological Standardization :
forty-second report.
(WHO technical report series ; 822)
1. Biological products - standards I. Series
ISBN 92 41208228 (NLM Classification: OW 800)
ISSN 0512-3054
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O World Health Organization 1992
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Contents
Introduction
General
Good manufacturing practices for biological products
Distribution of International Biological Standards and Reference Reagents
Revision of the publication Biological substances: International Standards
and Reference Reagents
lnternational reference materials: procedure for disposal of discontinued
materials
Vitamin D
Guidelines and requirements
Guidelines on quality assurance for biologicals
Monoclonal antibodies for use in humans
Requirements for influenza vaccine (inactivated): endotoxin content
Requirements for measles, mumps and rubella combined
vaccines (live)
Antibiotics
Gramicidin
Gentamicin
Requirements for antimicrobic susceptibility tests:
I. Agar diffusion tests using antimicrobic susceptibility discs
Antibodies
Anti-toxoplasma serum, human
Rabies immunoglobulin
Anti-poliovirus serum
Antigens
Rabies vaccine
Acellular pertussis vaccines
Vi typhoid vaccines
Yellow fever vaccine
Blood products
Alpha-thrombin, human
Plasma fibrinogen, human
Plasminogen-activator inhibitor-l (PAI-I)
Single-chain urinary-type plasminogen activator
Recombinant hirudins
Blood coagulation factor Vlll and von Willebrand factor
Protein S
Liver ferritin, human
Apolipoprotein A-l
Haemoglobin F and haemoglobin A,
Endocrinological and related substances
Human calcitonin
Porcine calcitonin
Thyroxine-binding globulin
Anti-thyroid microsome serum
Somatropin
Nerve growth factor
Epidermal growth factor
Basic fibroblast growth factor
Acidic fibroblast growth factor
Platelet-derived growth factor
Recombinant thyroid-stimulating hormone
Recombinant follicle-stimulating hormone
Insulin-like growth factor-binding protein
Tumour necrosis factor
Cytokines
Progress report
Interleukin-l receptor antagonist
Granulocyte/macrophage colony-stimulating factor
Granulocyte colony-stimulating factor
Macrophage colony-stimulating factor
Interleukin-3
Interleukin-4
Interleukin-5
Interleukin-7
Interleukin-8
Leukaemia inhibitory factor
Transforming growth factor beta
Annex l
Good manufacturing practices for biological products
Annex 2
Guidelines for national authorities on quality assurance for biological products
Annex 3
Guidelines for assuring the quality of monoclonal antibodies for use
in humans
Annex 4
Requirements for antimicrobic susceptibility tests:
I. Agar diffusion tests using antimicrobic susceptibility discs
(addendum 1991)
Annex 5
Laboratories approved by WHO for the production of yellow fever vaccine
Annex 6
Biological substances: International Standards and Reference Reagents
Annex 7
Requirements for biological substances and other sets of recommendations
WHO Expert Committee on Biological Standardization
Geneva, 22-29 October 1991
Members
Dr D.H. Calam, Head, Chemistry Division, National lnstitute for Biological Standards
and Control, Potters Bar, Herts., England (Rapporteur)
Professor E. M. Essien, Director, National lnstitute for Medical Research, Yaba,
Lagos, Nigeria
Dr J. Furesz, Director, Bureau of Biologics: Ottawa, Ontario, Canada
Professor I. Gust, Director, Research and Development, CSL Ltd., Victoria, Australia
(Chairman)
Dr Z. Khan: Principal Scientific Officer, Quality Control Division, National lnstitute of
Health, Islamabad, Pakistan
Mr J. Lyng, Head, Laboratory of Biological Standardization, State Serum Institute,
Copenhagen, Denmark
Professor N. V. Medunitsin, Director, Tarasevich State lnstitute for the
Standardization and Control of Medical Biological Preparations, Moscow, USSR
( Vice-chairman)
Dr H. Mirchamsy, Associate Director, Razi State lnstitute of Sera and Vaccines,
Teheran, Islamic Republic of Iran
Dr W. W. Wright, Senior Scientist, Drug Standards Division, United States
Pharmacopeia, Rockville, MD, USA
Mr Zhou Hai-jun, Director, National lnstitute for the Control of Pharmaceutical and
Biological Products, Beijing, China
Representatives of other organizations
Council of Europe
Mr J.-M. Spieser, European Pharmacopoeia Commission, Council of Europe,
Strasbourg, France
International Federation of Pharmaceutical Manufacturers Associations (IFPMA)
Dr H.-G. Lehmann, IFPMA, Geneva, Switzerland
Secretariat
Dr E. Esber, Associate Director for Research and Regulatory Coordination, Center
for Biologics Evaluation and Research, Food and Drug Administration, Bethesda,
M D, USA (Temporary Ao'viser)
Dr D. Magrath, Chief. Biologicals, WHO: Geneva, Switzerland (Secretary)
Dr P. L. Storring, Scientist, Department of Endocrinology, National lnstitute for
Biological Standards and Control, Potters Bar, Herts., England
(Temporary Adviser)
Dr W. G. van Aken, Medical Director, Central Laboratory of the Netherlands Red
Cross Blood Transfusion Service, Amsterdam, Netherlands (Temporary Adviser)
Dr H. J. M. van de Donk, Head, Control of Bacterial Vaccines, National lnstitute of
Public Health and Environmental Protection, Bilthoven, Netherlands
(Temporary Adviser)
Introduction
The WHO Expert Committee on Biological Standardization met in
Geneva from 22 to 29 October 1991. The meeting was opened on
behalf of the Director-General by Dr Hu Ching-Li, Assistant Director-
General.
Dr Hu emphasized the importance of the biological standardization
programme for countries with developing health programmes and stressed
the need for the Committee, in making recommendations, to take account
of the procedures essential for assuring the safety and eficacy of biological
products, but to avoid specifying unnecessarily stringent or restrictive
conditions.
General
Good manufacturing practices for biological products
The Committee noted that the WHO Secretariat had prepared a docu-
ment entitled "Good manufacturing practice for biological products"
Q3S/91.1656),' intended to provide guidance for biological products
supplementary to that given in the more general "Good manufacturing
practices for pharmaceutical products" (WHO Technical Report Series,
No. 823, 1992, Annex 1). After making some modifications to the draft
text, the Committee agreed that the document should be annexed to its
report (Annex 1).
Distribution of International Biological Standards
and Reference Reagents
The Committee noted the distribution of international reference materials
by the four main International Laboratories for Biological Standards
during 1990 (Table 1) (BS/91.1677). It noted a slight deche in the number
of standards distributed by comparison with 1989 (WHO Techcal
Report Series, No. 814, 1991, p. 3) and requested that for distributions
made during 1991 a more detaded analysis by product category be
provided. The Committee also requested the WHO Secretariat to obtain
similar information on the distribution of international reference
materials held and distributed on behalf of WHO by other cooperating
laboratories.
The Committee was informed that, in accordance with the request made in
' References prefixed ' ' BSI ..." are to unpublished working documents of the World Health
Organization. They are not issued to the general public, but a limited number of copies may be
available to professionally interested persons on application to Biologicals, World Health
Organization, 1211 Geneva 27, Switzerland.
Table 1
lnternational Biological Standards and Reference Reagents distributed in 1990
by the lnternational Laboratories for Biological Standards
a
Number of i tems distributed by lnternational Laboratories
WHO region for Biological Standards
Amsterdam Copenhagen Potters Bar Weybri dge Total % of total
for all
reqi ons
Africa 31 12 68 6 117 0.9
Ameri cas 1 34 354 979 12 1 479 11.0
Eastern
Mediterranean 0 126 14 5 145 1.1
Europe 2 612 1 545 6 171 131 10 459 77.9
South-East Asi a 7 132 599 9 747 5.6
Western Pacific 84 123 258 1 3 478 3.6
Total 2 868 2 292 8 089 176 13425
a Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam,
Netherlands: items distributed during the calendar year 1990. State Serum Institute, Copenhagen,
Denmark: items distributed during the calendar year 1990. National Institute for Biological Standards
and Control, Potters Bar, Herts., England: items distributed between 1 March 1990 and 30 April 1991.
Central Veterinary Laboratory, Weybridge, Surrey, England: items distributed during the calendar year
1990.
its forty-first report (WHO Technical Report Series, No. 814, 1991, p. 2),
the WHO Secretariat had obtained some information on the ways in which
international reference materials were used. Many users had stressed the
key role played by international reference materials in harmonizing the
quality of biologicals at both national and international levels. The
Committee emphasized that standardization and control of biologicals
could not be fully achieved without the provision of internationally
accepted reference materials, and that in the present era of vanishing
borders and increased demands for international harmonization, the role
of international biological reference materials was even more important
than in the past. In view of these factors, the Committee urged national
health administrations to continue to support the biological standardi-
zation programme at the highest level possible.
Revision of the publication Biological substances: lnternational
Standards and Reference Reagents
The Committee was informed that the revision of the WHO publication on
international reference materials referred to in its forty-first report (WHO
Techcal Report Series, No. 814, 1991, p. 4) had been published as
Biological substances: International Standards and Reference Reagents,
1990. The Committee noted some improvements in format and
acknowledged the contribution of the Secretariat in compiling this
publication.
International reference materials: procedure for disposal of
discontinued materials
The Committee noted some factors to be considered in disposing of stocks
of discontinued international reference materials (BS/91.1662), and
discussed the difficulties that might arise from uncontrolled distribution of
such preparations. The Committee therefore agreed that, in most cases, a
certain quantity of the discontinued preparation should be kept for
reference and hstorical purposes, and that the rest, depending on the
circumstances, should either be offered to any national control authority
retaining an interest in it, to the WHO Collaborating Centre for Chemical
Reference Substances, or to the original supplier, or be destroyed. The
Committee requested that any proposed action concerning stocks of
individual discontinued preparations be brought to its attention.
Vitamin D
The Committee noted that during the previous three years no requests had
been received for the second International Standard for Wanin D,
established in 1949 (WHO Techcal Report Series, No.2, 1950, p.10)
(BS/91.1666). The Committee was informed that preparations of vitamin
D can be fully characterized by chemical and physical means. The lack of
demand for the International Standard also reflected the replacement of
bioassays for measuring vitamin D in fish oils by physicochemical
methods. The Committee therefore decided to discontinue the
International Standard for -tarnin D. Because International Units of
%tarnin D might continue to be used for some time in the labelling of
certain preparations, the Committee requested the WHO Secretariat to
include, in the list of discontinued international biological reference
materials (see Annex 6), a note on equivalence, an International Unit of
D being widely taken to be equivalent to the activity in 25ng of
pure colecalciferol.
Guidelines and requirements
1
The Committee emphasized that its objective in adopting guidelines and
requirements for biological products was to draw attention to the factors
considered essential for assuring the availability of safe and efficacious
products. The Committee recognized that national circumstances might
demand additional or alternative procedures.
Guidelines on quality assurance for biologicals
The Committee noted that, in accordance with the undertaking given in its
forty-first report (WHO Technical Report Series, No. 814, 1991, p. 14), the
WHO Secretariat had prepared a revised draft of the guidelines for
national authorities and manufacturers on quality assurance for biological
products and had circulated the draft for comment (BW91.1655). The
Committee reviewed the draft and the comments received on it. Most of
the information directed to manufacturers had now been included in the
documents "Good manufacturing practices for pharmaceutical products"
(WHO Technical Report Series, No. 823, 1992, Annex 1) and "Good
manufacturing practices for biological products" (Annex 1). The
Committee therefore modified the draft text so that it was directed only to
national authorities and, after making further changes to it, agreed that it
should be annexed to its report under the title "Guidelines for national
authorities on quality assurance for biological products" (Annex 2).
The Committee was informed that consideration was being given to
publishing the requirements and guidelines relating to biological products
as a cumulative compendium separate from the Committee's reports. The
Committee recommended that the Secretariat prepare an additional
document addressing post-manufacturing and post-marketing issues, for
inclusion in such a compendium.
Monoclonal antibodies for use in humans
The Committee noted that the WHO Secretariat had prepared
requirements for monoclonal antibodies for clinical use in humans
(BW91.1657) following an informal consultation in February 1991 and
subsequent receipt of additional comments. After making some
modifications, the Committee adopted the document as "Guidelines for
assuring the quality of monoclonal antibodies for use in humans", and
agreed that it should be annexed to its report (Annex 3).
' For a summary list of all the requirements for biological substances and other sets of I
recommendations, see Annex 7.
Requirements for influenza vaccine (inactivated):
endotoxin content
The Committee noted that, since the revision in 1990 of the Requirements
for Influenza Vaccine (Inactivated) (WHO Technical Report Series,
No. 814, 1991, p. 38), evidence had been received that some commercially
available inactivated influenza vaccines contained variable amounts of
endotoxin, which might be expected to induce fever in some recipients
(EW91.1658). However, the clinical implication of this evidence was
unclear. It was recognized that the variable levels of endotoxin might
reflect differences in manufacturing practice. The Committee was
informed that the European Pharmacopoeia was considering the inclusion
of an upper endotoxin limit of 100 International Units per human dose in
its monograph on influenza vaccine (inactivated) and that some national
control authorities had imposed, or were considering imposing, other
limits. The Committee deferred a decision on inclusion of a recommended
upper limit for endotoxin in section A.5.5 of the Requirements for
Influenza Vaccine (Inactivated) until more information was available.
Requirements for measles, mumps and rubella combined vaccines
(live)
The Committee noted that the WHO Secretariat had prepared draft
Requirements for Measles, Mumps and Rubella Combined Vaccines
(Live) (EW91.1653 Rev.l) that combined the existing Requirements for
Measles Vaccine (Live) (WHO Technical Report Series, No.771, 1988,
Annex 5), Requirements for Mumps Vaccine (Live) (WHO Technical
Report Series, No. 760, 1987, Annex 7), and Requirements for Rubella
Vaccine (Live) (WHO Technical Report Series, No. 610, 1977, Annex 3,
and No. 658, 1981, Annex 12). The Committee was informed that,
following circulation of the draft to members of the Expert Advisory Panel
on Biological Standardization, a number of comments had been received
and that further modifications would be made to the text. The Committee
agreed that, in view of the confhcting comments received, the
neurovirulence tests for virus master seed lots should be retained in the
Requirements, and that the revised draft should be submitted to it at a
future meeting for possible adoption.
Antibiotics
Gramicidin
The Committee was informed that stocks of the International Reference
Preparation of Gramicidin were depleted (EW91.1663). Gramicidin is a
mixture of linear peptides, and despite the availability of chromatographic
methods for examining its composition, the need for a microbiological
assay is expected to continue.
The Committee therefore agreed that a replacement preparation was
needed and requested the National Institute for Biological Standards and
Control, Potters Bar, to obtain suitable material and to organize a
collaborative study.
Gentamicin
The Committee noted that stocks of the International Reference
Preparation of Gentamycin (International Nonproprietary Name:
gentamicin) were depleted (BW91.1664). Gentamicin is widely used and,
because it consists of a mixture of structurally related components, the
need to assay it microbiologically is expected to continue. The Committee
was informed that the composition of gentamicin from different sources
may vary and that differences in composition between a reference
preparation and a test sample may give rise to problems in the assay.
The Committee therefore requested the National Institute for Biological
Standards and Control, Potters Bar, to carry out a survey through national
control laboratories in order to identify sources of gentamicin, and to
establish whether the composition of gentamicin is specified and whether
difficulties have been observed with assays.
The Committee further requested the National Institute for Biological
Standards and Control, Potters Bar, to review the information received
and, if appropriate, to obtain suitable material to replace the International
Reference Preparation and organize a collaborative study.
Requirements for antimicrobic susceptibility tests
I. Agar diffusion tests using antimicrobic susceptibility discs
At its forty-first meeting, the Committee had requested the WHO
Secretariat to investigate other mechanisms, not involving the Committee,
by which the disc code list in the Requirements for Antimicrobic
Susceptibility Tests could be updated and published, and by which the
Requirements could be revised (WHO Technical Report Series, No. 814,
1991, p. 13). At its present meeting, the Committee again reviewed the need
for international recommendations for the identification of antimicrobial
agents and for the Requirements themselves. In view of the fact that the
Requirements, apart from the code list, had not been revised from some
years, that there was now no intention by the Committee to draft further
parts of the Requirements, and that other publications covering the same
subject had appeared more recently, the Committee agreed that the
Requirements for Antimicrobic Susceptibility Tests: I. Agar Diffusion
Tests Using Antimicrobic Susceptibility Discs (Requirements for
Biological Substances No. 26) should be discontinued. The Committee
nevertheless recommended that the list of disc codes should be
maintained, but decided that in the future it would not annex lists of codes
to its own report.
The Committee agreed that the centralized international assignment of
codes, publication of the code list, and its regular updating were essential
to avoid the likehhood of allocation of codes by individual manufacturers,
or at national or regional level, whch would probably result in different
codes being adopted for a single substance. The Committee recommended
that WHO should continue to maintain, revise and publish the code list,
and that an appropriate mechanism should be found to do so; this might
usefully be associated with the nomenclature programme for new drug
substances. The Committee noted that since the publication of the 1990
addendum to the Requirements for Antimicrobic Susceptibility Tests
(WHO TechnicalReport Series, No. 814,1991, p. 71), the WHO Secretariat
had received further requests for the allocation of codes for new
antimicrobial substances, and that a draft addendum had been prepared
(BS/91.1665). The Committee adopted this further addendum with minor
modifications, and agreed that it should be annexed to its report (Annex 4).
Antibodies
Anti-toxoplasma serum, human
The Committee was informed that stocks of the second International
Standard for Anti-Toxoplasma Serum, Human, established in 1980
(WHO Technical Report Series, No. 658, 1981, p. 14), were nearly
exhausted and that a replacement was needed. The Committee therefore
requested the State Serum Institute, Copenhagen, to obtain suitable
replacement material and to organize a collaborative study.
Rabies immunoglobulin
The Committee was informed that the individual blood samples used to
produce the only candidate replacement material for the current
International Standard for Rabies Immunoglobulin, referred to in its
forty-first report (WHO Technical Report Series, No. 814, 1991, p. 7), had
been pooled before a test for antibody to hepatitis C virus was available
and had not been tested. Taking into account the urgent need for a
replacement standard, the amount of immunoglobulin per ampoule, and
the fact that safety warnings would be provided with samples of the
replacement standard, the Committee requested the State Serum Institute,
Copenhagen, to continue with the organization of a collaborative study.
Anti-poliovirus serum
The Committee noted that nine laboratories in eight countries had
participated in the collaborative study referred to in its forty-first report
(WHO Techcal Report Series, No.814, 1991, p.7), organized by the
National Institute for Biological Standards and Control, Potters Bar, and
that the results had been analysed (BS/91.1660). The Committee noted
that the candidate reference material was a human serum containing
antibodies to all three poliovirus types and had been found to be negative
in tests for hepatitis B surface antigen (Hl3sAg) and for antibodies to
human immunodeficiency virus, but had not been tested for antibody to
hepatitis C virus. The Committee further noted that the study had revealed
significant interlaboratory differences in the relative potencies observed
when human sera were compared with hyperimmune monkey sera.
The Committee decided that, to avoid confusion, the material should be
established as the second International Standard, although it was a
trivalent preparation and replaced the three previously established
monovalent standards, and that it should be issued with a safety warning
that it had not been tested for antibody to hepatitis C virus.
The Committee therefore established the material studied, in ampoules
coded 66/202, as the second International Standard for Anti-Poliovirus
Serum Types 1,2 and 3 and, on the basis of the results of the collaborative
study, assigned an activity of
25 International Units of Anti-Poliovirus Serum (Type l), Human,
50 International Units of Anti-Poliovirus Serum (Type 2), Human, and
5 International Units of Anti-Poliovirus Serum (Type 3), Human
to the contents of each ampoule.
The Committee recommended that, to avoid the difficulty experienced in
estimating the neutralizing activity of human sera relative to a
hyperimmune monkey serum, national standards of anti-poliovirus serum
should be prepared using human sera.
Antigens
Rabies vaccine
The Committee noted the results of the collaborative study in
14 laboratories in eight countries referred to in its thirty-ninth report
(WHO Technical Report Series, No. 786, 1989, p. B), which compared
three different rabies vaccines (including the proposed replacement
reference material) with the International Standard for Rabies Vaccine in
imrnunogenicity assays in mice (NIH test) and in different antigenicity tests
measuring envelope glycoprotein, a major antigen in rabies vaccine
(BW91.1654). The Committee also noted the results of a collaborative
study in which 49 lots of rabies vaccines produced by four different
producers and representing six different combinations of rabies virus
strains and cell substrates were compared using the NIH test as well as in
v i m antigenicity tests for glycoprotein, primarily the single radial
immunodi•’•’usion test (BS/91.1661). Both studies confirmed that
glycoproteins from different viruses are immunologically distinct. The
relative glycoprotein estimates, although very reproducible, did not reflect
the relative potencies obtained in the NIH test when the vaccines
compared differed in regard to virus strain or cell substrate. The
Committee therefore concluded that the NM test should not be replaced
by tests for estimating glycoprotein content.
The Committee established the proposed replacement vaccine, in
ampoules coded PISRAV, as the fifth International Standard for Rabies
Vaccine
1
on the basis of the results obtained in the collaborative study
using the NIH test and, in accordance with the proposal contained in the
report of the study and agreed to by the participants, assigned a potency of
16 International Units of Rabies Vaccine to the contents of each ampoule.
The Committee noted the need to standardize tests for rabies virus
glycoprotein and ribonucleoprotein, which appear to be important for the
protective activity of rabies vaccine (BS/91.1659). In view of this, and
since glycoproteins and perhaps also ribonucleoproteins are to some
degree strain-specific and the replacement reference material was derived
from the Pitman-Moore (PM) strain of virus, the Committee also
established the material in ampoules coded PISRAV as the first
International Standard for Rabies PM-Glycoprotein and the first
International Standard for Rabies =rus PM-Ribonucleoprotein, and
assigned 10 International Units of Rabies Virus PM-Glycoprotein and 135
International Units of Rabies Virus PM-kbonucleoprotein to the contents
of each ampoule.
Acellular pertussis vaccines
The Committee was informed that acellular pertussis vaccines containing
several different antigens were undergoing clinical trial and that there
might be a need for reference preparations to enable these vaccines to be
uniformly controlled. The Committee concluded, however, that further
data would be required before a decision to prepare international
reference materials could be made and requested the WHO Secretariat to
monitor developments.
Vi typhoid vaccines
The Committee was informed that an informal WHO consultation had
been held on requirements for typhoid vaccines and that proposed
requirements would be circulated later.
' Strictly speaking, the proposed replacement reference material should have been established
as the "second" lnternational Standard since it replaces a material established i n 1983 (WHO
Technical Report Series, No. 700: 1984) as the first lnternational Standard. However, the first
lnternational Standard replaced the third International Reference Preparation, and had it been
possible in 1983 to anticipate the Committee's decision in 1986 that "when an international
reference preparation is replaced by a new preparalion designated as an international
standard, then the international standard should be numbered as the next in seqr;ence after
the preceding international reference preparation" (WHO Technical Report Series, No.760,
1987), the material would have been established as the fourth rather than the first lnternational
Standard.
Yellow fever vaccine
The Committee noted that further changes had been made to the list of
laboratories approved by WHO for the production of yellow fever vaccine
and agreed that the revised list should be annexed to its report (Annex 5).
Blood products
Alpha-thrombin, human
The Committee noted that the National Institute for Biological Standards
and Control, Potters Bar, had completed the analysis of the results of the
collaborative study referred to in its forty-first report (WHO Technical
Report Series, No. 814,1991, p. 9). This study, of a preparation of purified
human alpha-thrombin, had involved eight laboratories in five countries
(BW91.1669).
The Committee established the material studied, in ampoules coded
89/588, as the International Standard for Alpha-Thrombin, Human and,
on the basis of the results of the collaborative study and the agreement of
the participants, assigned an activity of 100 International Units of
Alpha-Thrombin, Human to the contents of each ampoule. This Standard,
which is of prime use for accurate calibration and precise measurement of
thrombin inhibitors, notably hirudin (p.ll), exists in addition to the
International Standard for Human Thrombin, established in 1975, which
continues to be of value for calibrating thrombins of unknown potency.
Plasma fibrinogen, human
The Committee noted that the results of the collaborative study of a
preparation of plasma fibrinogen, referred to in its forty-first report (WHO
Technical Report Series, No. 814, 1991, p. 10), had been analysed
(BS/91.1670). The results of the collaborative study, in which 22
laboratories in nine countries had participated, indicated a mean content of
2.4mg of plasma fibrinogen in each ampoule of the material studied, in
ampoules coded 89/644. The Committee noted also that the stability of
the preparation 'was being investigated in four laboratories. The
Committee deferred a decision on the establishment of the preparation as
the International Reference Reagent for Plasma Fibrinogen until
satisfactory stability data were available.
Plasminogen-activator inhibitor-l (PAI-1)
The Committee was informed that the measurement of plasrninogen-
activator inhibitor-1 (PAT-1) concentrations in plasma is important in
assessing the tendency to develop thrombotic disease and that availability
of a reference material would facilitate such measurements, which are
difficult because PAI-1 is present in plasma as a functional latent form,
as an active form and as complexes. The Committee was further informed
that the National Institute for Biological Standards and Control, Potters
Bar, was organizing a study of a candidate preparation, in ampoules
coded 87/512.
Single-chain urinary-type plasminogen activator
The Committee was informed that single-chain urinary-type plasminogen
activator was secreted by certain cell cultures and was under investigation
for the treatment of myocardial infarction; this form of urolunase required
activation to the two-chain form before it could be assayed. A limited study
using the International Standard for High Molecular Weight Urolnase
had indicated that it might be a suitable immunological assay standard.
A larger study was planned by the National Institute for Biological
Standards and Control, Potters Bar, under the auspices of the International
Society on Thrombosis and Hemostasis, to investigate whether this
International Standard was suitable for use in both functional and antigen
assays.
Recombinant hirudins
The Committee noted that recombinant hirudin was available from several
manufacturers and was under investigation for therapeutic use as an
anticoagulant (BS/91.1667). The Committee also noted that a
collaborative study had shown that the activity of natural and recombinant
hirudins could be assayed using the material established as the
International Standard for Alpha-Thrombin, Human (p. 10), but that the
interlaboratory reproducibility would be improved if a reference material
for hirudin were available. The Committee requested the National Institute
for Biological Standards and Control, Potters Bar, to investigate the
possibility of establishing such a preparation.
Blood coagulation factor Vlll and von Willebrand factor
The Committee was informed that, because of heavy demand, stocks of the
second International Standard for Factor VIII and von Willebrand Factor
in Plasma were being depleted and would require replacement. The
Committee therefore requested the National Institute for Biological
Standards and Control, Potters Bar, to obtain suitable material and
organize a collaborative study.
Protein S
The Committee noted that measurement of protein S concentrations in
plasma, in which it is present both free and bound to C4b-binding protein,
is useful in the clinical diagnosis of thrombotic disorders and that such
assays are frequently performed @S/91.1668). In the absence of an
International Standard, assays are calibrated with plasma pools or
commercial standards. The Committee agreed that a need existed for an
international reference material. However, a collaborative study of a
lyophilized plasma in 11 laboratories organized by the National Institute
for Biological Standards and Control, Potters Bar, had revealed that
current assay methods for protein S would require further evaluation
before a formal collaborative study could be organized.
Liver ferritin, human
The Committee noted that stoclts of the International Standard for Human
Liver Ferritin Protein were depleted (BW91.1678). It was informed that a
preparation in ampoules coded 80/578, included in the collaborative
study that formed the basis for establishing the current International
Standard, was available as a replacement. The Committee requested the
National Institute for Biological Standards and Control, Potters Bar, to
carry out a limited study on the preparation to confirm that the results of
the previous collaborative study were still valid.
The Committee noted that, in the collaborative study leading to the
establishment of the first International Standard for Human Liver Ferritin
Protein, preparations 80/602 (which became the International Standard)
and 80/578 contained ferritin from Liver and spleen, respectively
(BSh34.1457). The Committee further noted that in the majority of assays
for ferritin in the serum these two preparations were not immunologically
distinguishable. The Committee agreed that, if the preparation 801'578 was
found to be suitable as a replacement material for the current International
Standard for Human Liver Ferritin Protein, it would be appropriate to
establish it as the second International Standard for Ferritin.
The Committee stressed that, on any similar occasion in future (i.e. if a
preparation included in the original collaborative study was under
consideration as a replacement international reference material), it would
be important that limited comparative studies of the proposed
replacement material were performed against the existing International
Standard.
Apolipoprotein A-l
The Committee was informed that a report had been received by the WHO
Secretariat of a study, performed by the International Federation of
Clinical Chemistry (IFCC), proposing the establishment of a preparation
of apolipoprotein A-l in a serum matrix as an International Standard.
The Committee agreed that there were deficiencies in the report and
deferred a decision pending clarification.
The Committee was informed that there was an urgent need to harmonize
measurements of apolipoprotein A-l, which were increasingly used in
screening for cardiovascular disease. As an interim measure, the WHO
Secretariat would arrange for the proposed reference material to be made
available on request. The Committee noted that the IFCC report stated
that, when the contents of one vial of the proposed standard were
reconstituted with 1 m1 of distilled water, the resulting fluid contained the
equivalent of 1.5 g/litre of apolipoprotein A-l.
Haemoglobin F and haemoglobin A,
At its thirty-eighth meeting (WHO Technical Report Series, No. 771,1988,
pp. 24 & 25), the Committee recognized the need for international
reference materials for haemoglobin F and haemoglobin A,. At its present
meeting, the Committee was informed that the International Council for
Standardization in Haematology had obtained materials to serve as
candidate reference preparations for these haemoglobins, and had
confirmed their stability and organized collaborative studies. The
Committee was further informed that, when the analyses of the studies
were complete, portions of each batch would be offered to WHO for
possible adoption as International Standards.
Endocrinological and related substances
Human calcitonin
The Committee noted that, in accordance with the request made in its
forty-first report (WHO Technical Report Series, No. 814, 1991, p. l l ),
the National Institute for Biological Standards and Control, Potters Bar,
had obtained a preparation of human calcitonin suitable to serve as a
replacement for the International Reference Preparation of Human
Calcitonin for Bioassay and had arranged a collaborative study
(BW91.1675). The Committee noted that the material studied, in
ampoules coded 89/620, was of adequate stability, and established it
as the second International Standard for Human Calcitonin. On the
basis of the results of the collaborative study, involving 16 laboratories
in 12 countries, and the agreement of the participants, the Committee
assigned an activity of 17.5 International Units of Human Calcitonin to
the contents of each ampoule, based on estimates made by the rat
hypocalcaemia bioassay.
Porcine calcitonin
The Committee noted that, in accordance with the request made in its
forty-first report (WHO Technical Report Series, No. 814,1991, p. l l ), the
National Institute for Biological Standards and Control, Potters Bar, had
obtained a preparation of porcine calcitonin suitable to serve as a
replacement for the International Reference Preparation of Porcine
Calcitonin for Bioassay and had arranged a collaborative study
(BS/91.1674). The Committee noted that the material studied, in
ampoules coded 89/540, was of adequate stability as determined by
bioassay and established it as the second International Standard for
Porcine Calcitonin. On the basis of the results of the collaborative study,
involving 16 laboratories in 12 countries, and the agreement of the
participants, the Committee assigned an activity of 0.8 International Unit
of Porcine Calcitonin to the contents of each ampoule, based on estimates
made by the rat hypocalcaemia bioassay.
Thyroxine-binding globulin
The Committee noted that, in accordance with the request made in its
thirty-ninth report (W30 Technical Report Series, No. 786, 1989, p. 25),
the National Institute for Biological Standards and Control, Potters Bar,
had obtained a preparation of thyroxine-binding globulin suitable to serve
as an International Standard and had arranged a collaborative study in six
laboratories in four countries (BS/91.1671). The material studied, in
ampoules coded 88/638, had been assessed by immunologcal methods
and was of adequate stability. The Committee therefore established it as
the International Standard for Thyroxine-binding Globulin and, on the
basis of the results of the collaborative study and the agreement of the
participants, defined the activity of the contents of each ampoule as 30
International Units of Thyroxine-binding Globulin. The Committee noted
that the content of 30 International Units per ampoule was equivalent to
the nominal ampoule content of 30 pg of thyroxine-binding globulin as
estimated by ultraviolet spectrophotometry. However, the Committee
cautioned that such an equivalence might not apply to other preparations
of thyroxine-binding globulin.
Anti-thyroid microsome serum
The Committee noted that, in accordance with the request made in its
forty-first report (WHO Technical Report Series, No. 814, 1991, p. ll), the
National Institute for Biological Standards and Control, Potters Bar, had
provided information on the present demand for the preparation of
anti-thyroid microsome serum coded 66/387 and on its stability
(BS/91.1672). However, the Committee concluded that the data available
were insuficient to justify adoption of the preparation of anti-thyroid
microsome serum as an international reference material and requested the
National Institute for Biological Standards and Control, Potters Bar, to
consider whether further experimental studies were necessary.
Somatropin
The Committee noted that the collaborative study of a candidate
preparation of recombinant growth hormone (somatropin), referred to in
its thirty-ninth report (WHO Technical Report Series, No.786, 1989,
p.22), was in progress (BS/91.1673).
Nerve growth factor
The Committee was informed of the need for a reference material for
nerve growth factor and requested the National Institute for Biological
Standards and Control, Potters Bar, to obtain a suitable preparation and
organize a collaborative study.
Epidermal growth factor
The Committee noted that, in view of the discussion in its forty-first report
(WHO Technical Report Series, No. 814, 1991, p.l), the National Institute
for Biological Standards and Control, Potters Bar, had obtained four
candidate reference preparations of epidermal growth factor (BSI'
91.1676). The Committee also noted that three of the preparations had
been ampouled and that stability studies were in progress.
Basic fibroblast growth factor
The Committee noted that, following the discussion at its forty-first
meeting (WHO Technical Report Series, No. 814,1991, p. l), the National
Institute for Biological Standards and Control, Potters Bar, had obtained
and ampouled three candidate reference preparations of basic fibroblast
growth factor (BSI'91.1676). The Committee also noted that preliminary
stability studies were complete and that a collaborative study had
commenced.
Acidic fibroblast growth factor
The Committee noted that, in view of the discussion in its forty-first report
(WHO Technical Report Series, No. 814,1991, p. l), the National Institute
for Biological Standards and Control, Potters Bar, had obtained two
candidate reference preparations of acidic fibroblast growth factor, but
that further preparations were being sought before a collaborative study
would commence (BSI'91.1676).
Platelet-derived growth factor
The Committee noted that, following the discussion at its forty-first
meeting (WHO Technical Report Series, No. 814,1991, p.l), the National
Institute for Biologcal Standards and Control, Potters Bar, had obtained a
candidate reference preparation of platelet-derived growth factor, but that
further preparations were being sought before a collaborative study would
commence (BY91.1676).
Recombinant thyroid-stimulating hormone
The Committee was informed that, because of the dif6culty of obtaining
thyroid-stimulating hormone of pituitary origin, manufacturers would
make increasing use of preparations of recombinant thyroid-stimulating
hormone as standards in immunoassay kits. The Committee requested the
National Institute for Biological Standards and Control, Potters Bar, to
obtain suitable material and to organize a collaborative study to establish
whether preparations of recombinant hormone could be calibrated
adequately by immunoassay in terms of the existing International
Reference Preparation of pituitary TSH.
Recombinant follicle-stimulating hormone
The Committee was informed that recombinant follicle-stimulating
hormone intended for therapeutic use was available from several sources,
and that calibration of these products against existing international
reference materials containing follicle-stimulating hormone of pituitary or
urinary origin might be inappropriate. The Committee therefore requested
the National Institute for Biological Standards and Control, Potters Bar, to
organize a study to establish whether a new international reference
material was required for the recombinant hormone.
Insulin-like growth factor-binding protein
The Committee was informed that there was a rapidly growing interest in
insulin-like growth factor-binding protein, which was available as a
product of recombinant-DNA technology, and in its potential applications
for diagnosis and therapy. The Committee recognized the need for an
international reference material and requested the National Institute for
Biological Standards and Control, Potters Bar, to obtain suitable materials
and to organize a collaborative study.
Tumour necrosis factor
The Committee noted that the results of the collaborative study of a
preparation of recombinant human tumour necrosis factor alpha
(rhTNF-a), referred to in its forty-first report (WHO Technical Report
Series, No. 814,1991, p.12), had been analysed (BW91.1681). The results
of the study, performed in 20 laboratories in eight countries, had shown
that a preparation with the full molecular structure of rhTNF-a was the
most suitable for biological assays of TNF. The Committee therefore
established the material, in ampoules coded 87/650, as the International
Standard for Human Tumour Necrosis Factor Alpha, and defined its
potency as 40 000 International Units of Human Tumour Necrosis Factor
Alpha per ampoule.
The collaborative study had revealed that the International Standard might
be inappropriate for the assay of preparations of TNF-a of modified
structure, and that it was unsuitable for use as a reference material for
assays of human tumour necrosis factor beta (hTNF-P) and of
recombinant mouse tumour necrosis factor alpha (rmTNF-a). Because of
the pressing need for reference materials for these last two substances, the
two preparations that were included in the collaborative study will be
available from the National Institute for Biological Standards and Control,
Potters Bar, with arbitrary unitages assigned to them, until International
Standards are established. The Committee emphasized that the units for
rhTNF-a, hTNF-P and rmTNF-a do not correlate with one another.
The Committee was informed of a collaborative study being organized by
WHO of the assay of TNF in sera from patients with various diseases,
including malaria and meningitis, in order to assess the prognostic values
of such assays. The Committee would be advised in due course of the
results of the study.
Cytokines
Progress report
In view of the rapid developments in this field, steps had been taken to
obtain a number of candidate materials and assess their suitability to serve
as International Standards. The Committee noted that ampouled
preparations of cytokines for which collaborative studies had been
completed could be obtained from the National Institute for Biological
Standards and Control, Potters Bar, and the National Institutes of Health,
Bethesda, before formal establishment as international reference
materials.
Interleukin-l receptor antagonist
The Committee was informed of the need for a reference material for
interleukin-l receptor antagonist and requested the National Institute for
Biological Standards and Control, Potters Bar, to obtain a suitable
preparation and organize a collaborative study.
Granulocyte/macrophage colony-stimulating factor
The Committee noted that the collaborative study on the proposed
international reference material for granulocyte/macrophage colony-
stimulating factor, referred to in its forty-first report (WHO Technical
Report Series, No.814, 1991, p.12), was complete and that the results
were being analysed (l3S/91.1679 & 80).
Granulocyte colony-stimulating factor
The Committee noted that the collaborative study on the proposed
international reference material for granulocyte colony-stimulating factor,
referred to in its forty-first report (WHO Technical Report Series, No. 814,
1991, p.12), was complete and that the results were being analysed
(BS/91.1679 &80).
Macrophage colony-stimulating factor
The Committee was informed that, in accordance with the request made in
its thirty-ninth report (WHO Technical Report Series, No. 786, 1989,
p.26), the National Institute for Biological Standards and Control,
Potters Bar, had obtained three candidate reference preparations of
macrophage colony-stimulating factor, and a collaborative study was
in progress involving a wide variety of assay systems.
The Committee was informed that, in accordance with the request
made in its thirty-ninth report (WHO Technical Report Series, No.786,
1989, p. X) , the National Institute for Biologcal Standards and Control,
Potters Bar, had obtained and ampouled three candidate reference
preparations of interleulun-3. The Committee was also informed that
stability studies were complete and that a collaborative study had been
organized.
The Committee was informed that, in accordance with the request made in
its thirty-ninth report (WHO Technical Report Series, No.786, 1989,
p. 26), the National Institute for Biological Standards and Control, Potters
Bar, had obtained and ampouled three candidate reference preparations of
interleukin-4. The Committee was also Informed that stability studies were
complete and that a collaborative study had been organized.
The Committee was informed that, in view of the need for a reference
preparation of interleukin-5, the National Institute for Biological
Standards and Control, Potters Bar, had obtained and ampouled a
candidate preparation and a stability study was in progress.
The Committee was informed that, in view of the need for a reference
preparation of interleulun-7, the National Institute for Biological
Standards and Control, Potters Bar, had obtained and ampouled two
candidate preparations and stability studies were in progress.
The Committee was informed that, in accordance with the request made in
its thirty-ninth report (WHO Technical Report Series, No.786, 1989,
p. 26), the National Institute for Biological Standards and Control, Potters
Bar, had obtained and ampouled two candidate reference preparations of
interleukin-8. The Committee was also informed that stability studies were
complete and that a collaborative study would be organized.
Leukaemia inhibitory factor
The Committee was informed that, in view of the need for a reference
preparation of leukaemia inhibitory factor, the National Institute for
Biological Standards and Control, Potters Bar, had obtained and
ampouled a candidate preparation and stability studies were in progress.
Transforming growth factor beta
The Committee was Informed that, in view of the need for a reference
preparation of transforming growth factor beta, the National Institute for
Biological Standards and Control, Potters Bar, had obtained and
ampouled a candidate preparation and a stability study was in progress.
O World Health Organization
WHO Technical Report Series, No. 822, 1992
Annex 1
Good manufacturing practices for
biological products
1. Scope of these guidelines
2. Principles
3. Personnel
4. Premises and equipment
5. Animal quarters and care
6. Production
7. Labelling
8. Lot processing records (protocols) and distribution records
9. Quality assurance and quality control
Authors
Acknowledgements
References
I . Scope of these guidelines
These guidelines are intended to complement those provided in "Good
manufacturing practices for pharmaceutical products" (1).
The regulatory procedures necessary to control biological products are in
large part determined by the sources of products and methods of
manufacture. Manufacturing procedures within the scope of these
guidelines include:
- growth of strains of microorganisms and eukaryotic cells,
- extraction of substances from biological tissues, including human,
animal and plant tissues (allergens),
- recombinant DNA (rDNA) techniques,
- hybridoma techniques,
- propagation of microorganisms in embryos or animals.
Biological products manufactured by these methods include allergens,
antigens, vaccines, hormones, cytokines, enzymes, human whole blood
and plasma derivatives, immune sera, immunoglobulins (including
monoclonal antibodies), products of fermentation (including products
derived from rDNA) and diagnostic agents for in vitro use.
2. Principles
The manufacture of biological products shall be undertaken in accordance
with the basic principles of good manufacturing practices (GMP). The
points covered by these guidelines should therefore be considered
supplementary to the general requirements set out in "Good
manufacturing practices for pharmaceutical products" (l), and relate
specifically to the production and control of biological products. In
drawing up these guidelines, due consideration was given to the draft
"Guidelines for national authorities on quality assurance for biological
products", the final version of which appears as Annex 2 to the forty-second
report of the WHO Expert Committee on Biological Standardization (2).
The way in whch biologcal products are produced, controlled and
administered makes some particular precautions necessary. Unlike
conventional pharmaceutical products, which are normally produced and
controlled using reproducible chemical and physical t echques, biological
products are manufactured by methods involving biological processes and
materials, such as cultivation of cells or extraction of material from living
organisms. These processes display inherent variability, so that the range
and nature of by-products are variable. For t hs reason, in the manufacture
of biological products full adherence to GMP is necessary for all
production steps, beginning with those from whch the active ingredients
are produced.
Control of biological products nearly always involves biological techniques
that have a greater variability than physicochemical determinations.
In-process controls take on a great importance in the manufacture of
biological products because certain deficiencies may not be revealed by
testing the h s h e d product.
The present guidelines do not lay down detailed requirements for specific
classes of biological products, and attention is therefore directed to
other guidance issued by WHO, and in particular to the Requirements
for Biologcal Substances, which include requirements for vaccines
(2, Annex 7).
3. Personnel
3.1 The manufacturing establishment and its personnel shall be under the
authority of a person who has been trained in the techniques used in
manufacturing biological substances and who possesses the scientific
knowledge upon whch the manufacture of these products is based. The
personnel shall include specialists with training appropriate to the
products made in the establishment.
3.2 Personnel required to work in clean and aseptic areas should be
selected with care, to ensure that they may be relied upon to observe the
appropriate codes of practice and are not subject to any disease or
condition that could compromise the integrity of the product
microbiologically or otherwise. High standards of personal hygiene and
cleanliness are essential. Staff should be instructed to report any
conditions (e.g. diarrhoea, coughs, colds, infected skin or hair, wounds,
fever of unknown origin) that may cause the shedding of abnormal
numbers or types of organisms into the working environment. Health
checks on personnel for such conditions should be required before
employment and periodically thereafter. Any changes in health status that
could adversely affect the quality of the product shall preclude the person
concerned from working in the production area.
3.3 Only the minimum number of personnel required should be present in
clean and aseptic areas when work is in progress. Inspection and control
procedures should be conducted from outside these areas as far as
possible.
3.4 During the worlung day, personnel shall not pass from areas where
live microorganisms or animals are handled to premises where other
products or organisms are handled unless clearly defined decontamination
measures, including a change of clothing and shoes, are followed. Persons
not concerned with the production process should not enter the
production area except for essential purposes, and in that case they
shall be supplied with sterile protective clothing.
3.5 The staff engaged in the manufacturing process should be separate
from the staff responsible for animal care.
3.6 The names and qualifications of those responsible for approving lot
processing records (protocols) should be registered with the national
control authority.
3.7 To ensure the manufacture of high-quality products, personnel should
be trained in good manufacturing and laboratory practices in appropriate
fields such as bacteriology, virology, biometry, chemistry, medicine,
immunology and veterinary medicine.
3.8 Training records should be maintained and periodic assessments of
the effectiveness of training programmes should be made.
3.9 All personnel engaged in production, maintenance, testing and animal
care (and inspectors) should be vaccinated with appropriate vaccines and,
where appropriate, be submitted to regular testing for evidence of active
tuberculosis. Apart from the obvious problem of exposure of staff to
infectious agents, potent toxins or allergens, it is necessary to avoid the risk
of contamination of a production batch with these agents.
3.10 Where BCG vaccines are being manufactured, access to production
areas shall be restricted to staff who are carefully monitored by regular
health checks. In the case of manufacture of products derived from human
blood or plasma, vaccination of workers against hepatitis B is
recommended.
4. Premises and equipment
4.1 As a general principle, buildings must be located, designed,
constructed, adapted and maintained to suit the operations to be carried
out within them. Laboratories, operating rooms and all other rooms and
buildings (including those for animals) that are used for the manufacture of
biological products shall be designed and constructed of materials of the
highest standard so that cleanliness, especially freedom from dust, insects
and vermin, can be maintained.
4.2 Interior surfaces (walls, floors and ceilings) shall be smooth and free
from cracks; they shall not shed matter and shall permit easy cleaning and
disinfection. Drains should be avoided wherever possible and, unless
essential, should be excluded from aseptic areas. Where installed they
should be fitted with effective, easily cleanable traps and with breaks to
prevent back-flow. The traps may contain electrically operated heating
devices or other means for disinfection. Any floor channels should be
open, shallow and easily cleanable and be connected to drains outside the
area in a manner that prevents ingress of microbial contaminants.
4.3 Sinks shall be excluded from aseptic areas. Any sink installed in other
clean areas shall be of suitable material such as stainless steel, without an
ovedow, and be supplied with water of potable quality. Adequate
precautions shall be taken to avoid contamination of the drainage system
with dangerous effluents. Airborne dissemination of pathogenic
microorganisms and viruses used for production and the possibility of
contamination by other types of viruses or substances during the
production process, including those from personnel, shall be avoided.
4.4 Lighting, heating, ventilation and, if necessary, air-conditioning
should be designed to maintain a satisfactory temperature and relative
humidity, to minimize contamination and to take account of the comfort of
personnel working in protective clothmg. Buildings shall be in a good state
of repair. The condition of the buildings should be reviewed regularly and
repairs carried out when and where necessary. Special care should be
exercised to ensure that building repair or maintenance operations do not
compromise products. Premises should provide sufficient space to suit the
operations to be carried out, allowing an efficient flow of work and
effective communication and supervision. All buildings and rooms shall be
clean and sanitary at all times. If rooms intended for the manufacture of
biological substances are used for other purposes, they shall be cleaned
thoroughly and, if necessary, sanitized before the manufacture of
biological substances is resumed. Areas used for processing animal tissue
materials and microorganisms not required for the current manufacturing
process and for performing tests involving animals or microorganisms
must be separated from premises used for nlanufachuing sterile biological
products and have completely separate ventilation systems and separate
staff.
4.5 If certain products are to be produced on a campaign basis, the layout
and design of the premises and equipment shall permit effective
decontamination by fumigation, where necessary, as well as cleaning and
sanitizing after the production campaign.
4.6 Seed lots and cell banks used for the production of biological products
should be stored separately from other material. Access should be
restricted to authorized personnel.
4.7 Live organisms shall be handled in equipment that ensures that
cultures are maintained in a pure state and are not contaminated during
processing.
4.8 Products such as lulled vaccines, including those made by rDNA
techniques, toxoids and bacterial extracts may after inactivation be
dispensed into containers on the same premises as other sterile biological
products, providing that adequate decontamination measures are taken
after filling, including, if appropriate, sterilization and washing.
4.9 Spore-forming organisms shall be handled in facilities dedicated to
this group of products until the inactivation process is accomplished. For
Bacillus anthracis, Clostridium botulinum and Clostridium tetani, strictly
dedicated facilities should be utilized for each individual product. Where
campaign manufacture of spore-forming organisms occurs in a facility or
suite of facilities, only one product should be processed at any one time.
4.10 Dedicated facilities and equipment shall be used for the manufacture
of medicinal products derived from human blood or plasma.
4.11 All containers of biological substances, regardless of the stage of
manufacture, shall be identified by securely attached labels. Cross-
contamination should be prevented by adoption of some or all of the
following measures:
- processing and filling in segregated areas;
- avoiding manufacture of different products at the same time, unless
they are effectively segregated;
- containing material transfer by means of airlocks, air extraction,
clothing change and careful washmg and decontamination of
equipment;
- protecting against the rislts of contamination caused by recirculation of
untreated air, or by accidental re-entry of extracted air;
- using "closed systems
7
' of manufacture;
- taking care to prevent aerosol formation (especially by centrifugation
and blending);
- excluding pathological specimens sent in for diagnosis from areas used
for manufacturing biological substances;
- using containers that are sterilized or are of documented low
"bioburden".
4.12 Positive-pressure areas should be used to process sterile products,
but negative pressure is acceptable in specific areas where pathogens are
processed. In general, any organisms considered to be pathogenic should
be handled w i t h specifically designed areas under negative pressures, in
accordance with containment requirements for the product concerned.
4.13 Au-handling units should be dedicated to the processing area
concerned. Air from operations involving pathogens shall not be
recirculated and; in the cases of organisms in a group above Rs k Group 2
(3); shall be exhausted through sterilizing filters that are regularly checked
for performance.
4.14 Specific decontamination systems should be considered for effluent
when infectious and potentially infectious matelials are used for
production.
4.15 Pipework, valves and vent filters shall be properly designed to
facilitate cleaning and sterilization. Valves on fermentation vessels shall be
completely steam-sterihzable. Ar-vent filters shall be hydrophobic and
shall be validated for their designated use.
4.16 Small stocks of substances that have to be measured or weighed
during the production process (e.g. buffers) may be kept in the production
area, provided that they are not returned to the general stocks. Otherwise,
dry materials used to formulate buffers, culture media, etc. should be
weighed and put into solution in a contained area outside the purification
and aseptic areas in order to minimize particulate contamination of the
product.
5. Animal quarters and care
1
5.1 Animals are used for the manufacture and control of a number
of biological products. Animals shall be accommodated in separate
buildings with self-contained ventilation systems. The buildings' design
and construction materials shall permit maintenance in a clean and
sanitary condition free from insects and vermin. Facilities for animal care
shall include isolation units for quarantine of incoming animals and
provision for vermin-free food storage. Provision shall also be made for
animal inoculation rooms, which shall be separate from the postmortem
rooms. There shall be facilities for the disinfection of cages, if possible by
steam, and an incinerator for disposing of waste and of dead animals.
5.2 The health status of animals from which starting matelials are derived
and of those used for quality control and safety testing should be
monitored and recorded. Staff employed in animal quarters must be
provided with special cl ot hg, changing facilities and showers. Where
monkeys are used for the production or quality control of biological
products; special consideration is required, as laid down in the revised
Requirements for Biological Substances No. 7 (Requirements for Polio-
myelitis Vaccine (Oral)) (5).
General requirements for animal quarters, care and quaractine are given in reference 4
6. Production
6.1 Standard operating procedures shall be available and maintained up
to date for all manufacturing operations.
6.2 Specifications for starting materials should include details of their
source, origin and method of manufacture and of the controls applied, in
particular microbiological controls, to ensure their suitability for use.
Release of a finished product is conditional on satisfactory results being
obtained in the tests on starting materials.
6.3 Media and cultures shall be added to fermenters and other vessels
under carefully controlled conditions to avoid contamination. Care shall
be taken to ensure that vessels are correctly connected when cultures are
added.
6.4 If possible, media should be sterilized in situ. In-line sterilizing filters
for routine addition of gases, media, acids, alkalis, defoaming agents, etc. to
fermenters should be used where possible.
6.5 Careful consideration should be given to the validation of sterilization
methods.
6.6 When an inactivation process is performed during manufacture,
measures should be taken to avoid the risk of cross-contamination
between treated and untreated products.
6.7 A wide variety of equipment is used for chromatography; in general
such equipment should be dedicated to the purification of one product and
should be sterilized or sanitized between batches. Problems of
decontamination and purification may arise through repeated use of the
same equipment at the same or different stages of processing. The life span
of columns and the sterilization method shall be defined. Particular care
should be given to monitoring microbial loads and endotoxins.
7. Labelling
7.1 All products shall be clearly identified by labels. The labels used must
remain permanently attached to the containers under all storage
conditions and an area of the container should be left uncovered to allow
inspection of the contents. If the final container is not suitable for labelling
(for example a capillary tube), it should be in a labelled package.
7.2 The information given on the label on the container and the label on
the package shall be approved by the national control authority.
7.3 The label on the container shall show:
- the name of the drug product;
- a list of the active ingredients and the amount of each present, with a
statement of the net contents, e.g. number of dosage units, weight or
volume;
- the batch or final lot number assigned by the manufacturer;
- the expiry date;
- recommended storage conditions or handling precautions that may be
necessary;
- directions for use, and warnings and precautions that may be necessary;
- the nature and amount of any substance used in the preparation of the
biological product that is likely to give rise to an adverse reaction in
some recipients;
- the name and address of the manufacturer or the company and/or the
person responsible for placing the drug on the market.
7.4 The label on the package shall, in addition to the information shown
on the label on the container, show at least the nature and amount of any
preservative or additive in the product.
7.5 The leaflet in the package should provide instructions for the use of
the product, and mention any contraindications or potential adverse
reactions.
8. Lot processing records (protocols) and distribution records
8.1 Processing records of regular production lots must provide a complete
account of the manufacturing history of each lot of a biological
preparation, showing that it has been manufactured, tested, dispensed into
containers and distributed in accordance with the licensed procedures.
8.2 A separate processing record should be prepared for each lot of
biological product, and should include the following information:
- the name and dosage of the product;
- the date of manufacture;
- the lot identification number;
- the complete formulation of the lot, including identification of seed or
starting materials;
- the batch number of each component used in the formulation;
- the yield obtained at different stages of manufacture of the lot;
- a duly signed record of each step followed, precautions taken and
special observations made throughout the manufacture of the lot;
- a record of all in-process control tests and of the results obtained;
- a specimen of the label;
- identification of packaging materials, containers and closures used;
- a dated signature of the expert responsible for approving the
manufacturing operations;
- an analytical report, dated and signed by the responsible expert,
showing whether the lot complies with the specifications described in
the standard operating procedure registered with the national control
authority;
- a record of the decision regarding the release or rejection of the lot by
the quality-control department and, if the lot is rejected, a record of its
disposal or utilization.
8.3 The records shall be of a type approved by the national control
authority. They shall be retained for at least two years after the expiry date
of a lot or batch of a biological product and be available at all times for
inspection by the national control authority.
8.4 Records must make it possible to trace all steps in the manufacture
and testing of a lot, and should include records of sterilization of all
apparatus and materials used in its manufacture. Distribution records must
be kept in a manner that permits rapid recall of any particular lot, if
necessary.
9. Quality assurance and quality control
9.1 The quality-assurance and/or quality-control department should have
the following principal duties:
- to prepare detailed instructions for each test and analysis;
- to ensure adequate identification and segregation of test samples to
avoid mix-up and cross-contamination;
- to ensure that environmental monitoring and equipment validation are
conducted as appropriate for evaluating the adequacy of the
manufacturing conditions;
- to release or reject raw materials and intermediate products, if
necessary;
- to release or reject packaging and labelling materials and the final
containers in which drugs are to be placed;
- to release or reject each lot of finished preparation;
- to evaluate the adequacy of the conditions under which raw materials,
intermediate products and finished biological preparations are stored;
- to evaluate the quality and stability of finished products and, when
necessary, of raw materials and intermediate products;
- to establish expiry dates on the basis of the validity period related to
specified storage conditions;
- to establish and, when necessary, revise control procedures and
specifications; and
- to be responsible for the examination of returned preparations to
determine whether such preparations should be released, reprocessed
or destroyed; adequate records of the distribution of such preparations
should be maintained.
9.2 A manufacturer's quality-control laboratory shall be separated from
the production area and ideally should be in a separate building. The
control laboratory should be designed and equipped and of such a size as
to be a self-contained entity, with adequate provision for the storage of
documents and samples, preparation of records and performance of the
necessary tests.
9.3 In-process controls play a specially important role in ensuring the
consistent quality of biological products. Tests that are crucial for quality
control but that cannot be carried out on the finished product shall be
performed at an appropriate stage of production.
9.4 Performance of all qualitative and quantitative tests mentioned in the
specifications for starting materials may be replaced by a system of
certificates issued by the producer of the starting material, provided that:
- there is a history of reliable production,
- the producer is regularly audited, and
- at least one specific identity test is conducted by the manufacturer of the
h a 1 product.
9.5 Samples of intermediate and final products shall be retained in
sufficient amount and under appropriate storage conditions to allow the
repetition or confirmation of a batch control. Howeveq reference samples
of certain starting materials, e.g. components of culture media, need not
necessarily be retained.
9.6 Certain operations require the continuous monitoring of data during a
production process, for example monitoring and recording of physical
parameters during fermentation.
9.7 Special consideration needs to be given to the quality-control
requirements arising from production of biological products by
continuous culture.
Authors
The first draft of "Good manufacturing practices for biological products" was prepared
in January 1991 by Dr V. P. Grachev, Scientist and Dr D.I. Magrath, Chief, Biologicals,
WHO, Geneva, Switzerland.
Acknowledgements
Acknowledgements are due to the following experts for their comments and advice on
the draft of "Good manufacturing practices for biological products": Professor
I. Addae-Mensah, Chemistry Department, University of Ghana, Accra, Ghana;
Professor H. Blume, German Pharmacists' Central Laboratory, Eschborn, Germany;
Dr A. Fenyves, Paul Ehrlich Institute, Langen, Germany; Dr C. Guthrie, General
Manager, Blood Products Division, CSL Ltd., Parkville, Australia; Dr U. Ihrig, German
Pharmacists' Central Laboratory, Eschborn, Germany; Mr K. Kawamura, Takeda
Chemical lndustries Ltd., Nihonbashi, Chuo-ku, Tokyo, Japan; Mr L. G. Kinnander,
Chief, Pharmaceutical Industries Ltd.: Nihonbashi, Chuo-ku, Tokyo: Japan; Mrs
S. F. Langlois, Director, Regulatory Affairs: Connaught Laboratories Ltd., A Pasteur
Merieux Company, Willowdale, Ontario, Canada; Mr ?. Lemoine, institute of Hygiene
and Epidemiology, Brussels, Belgium; Mr J. Lyng, State Serum Institute,
Copenhagen, Denmark; Professor N.V. Medunitsin, Director, Tarasevich State Institute
for the Standardization and Control of Medical Biological Preparations, Moscow,
USSR; Dr R. Netter, Paris, France; Professor A. A. Olaniyi: Pharmaceutical &
Chemistry Department, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria.
References
1. Good manufacturing practices for pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations. Thirty-second
Report. Geneva, World Health Organization, 1992 (WHO Technical Report Series,
No.823), Annex l .
2. WHO Expert Committee on Biological Standardization. Forty-second Report.
Geneva, World Health Organization, 1992 (WHO Technical Report Series,
No. 822).
3. Laboratory biosafety manual, 2nd ed. Geneva, World Health Organization, in
press.
4. Quality management for chemical safety testing. Geneva, World Health
Organization, 1992 (Environmental Health Criteria, No.141).
5. WHO Expert Committee on Biological Standardization. Fortieth Report. Geneva,
World Health Organization, 1990 (WHO Technical Report Series, No. BOO),
Annex 1.
0 World Health Organization
WHO Technical Report Series, No.822, 1992
Annex 2
Guidelines for national authorities on quality
assurance for biological products
1. Scope 31
2. Introduction 31
3. General considerations 33
4. Structure of a national control authority for biological products 34
5. Procedures for approval of manufacturers and products 35
6. The national control laboratory 37
7. Post-licensing monitoring of products 39
8. Procedures for approval of imported products 40
Authors 42
Acknowledgements 43
References 43
Appendix 1
Model certificate of approval of a biological product 45
Appendix 2
Model certificate for the release of a lot or lots of a biological product 46
I . Scope
This document describes measures for assuring the safety and efficacy of
biological products intended for use in humans. Its aim is to provide
general guidelines for national health authorities on quality assurance for
biological products, except those used solely as i?z vi t ~o diagnostic agents.
The concepts and principles have been harmonized with those of the
Requirements for Biological Substances and other related sets of
recommendations published by WHO (1). Though it is diEcult to provide
a set of guidelines applicable to all national situations, an attempt has been
made to cover a range of possibilities; the principles on whch this
document is based may assist in the development of national guidelines.
2. Introduction
Since the publication by IVHO in 1981 of a document entitled "The
national control of vaccines and sera'' (2): it has become apparent that it
would be helpful to provide updated guidance for countries wishing to
develop or improve quality-assurance procedures for biological products.
In addition, technological developments in the production of biologcals
and the availability of new analytical methods for determining their quality
have made evident the need for a further revision of the Requirements for
Biological Substances No. l (General Requirements for Manufacturing
Establishments and Control Laboratories), published in 1966 (3). The
present guidelines reflect the decision to combine parts of these two
documents into a single text.
National regulatory authorities have the duty to ensure that available
pharmaceutical products, whether imported or manufactured locally, are
of the required quality. This is particularly difficult for biological products,
the quality of which cannot be established entirely by tests on the material
in the final container. The national authority has the responsibility to
confirm that the manufacturer is adhering to the approved standards of
good manufacturing practice and to national and other requirements for
manufacture and quality control specific to the product. The mechanism
by which national authorities confirm the assurance of quality provided by
the manufacturer may depend on the resources available and whether the
product is manufactured locally or imported.
In general biological products are distinguished from other drugs by being
derived from living organisms (ranging from normal or genetically
modified microorganisms to humans), and frequently have a complex
molecular structure. They require special quality considerations because
of the biological nature of: (a) the starting materials, and/or (b) the
manufacturing process, and/or (c) the test methods needed to characterize
batches of the product.
Recognizing these difficulties and the need for international harmo-
nization of quality standards, WHO, largely through its Biologicals unit,
has a number of activities related to the quality assurance of biological
products used for the diagnosis, prevention and treatment of diseases.
These include: (a) publishing in the WHO Technical Report Series the
reports of expert groups, which may include documents such as this one
that constitute requirements or guidelines for use by national authorities;
(b) organizing the distribution of International Standards and other
reference materials for biological substances, which allow the
characterization and assay of products in terms of internationally accepted
units; (c) providing advice on the preparation of national reference
materials; (d) advising and assisting Member States in the establishment
and functioning of structures for national control purposes, e.g. by
organizing visits by experts and assisting with programmes of training and
research in relation to these activities; and (e) arranging scientific meetings
to provide an up-to-date and scientifically valid consensus on topics
relating to quality assurance that are generally applicable to Member
States throughout the world.
Developments in biological products have been extremely rapid in recent
years, and the potential of such products for improving health care on a
global scale is immense. There is an urgent need to match technological
advances with appropriate mechanisms for assuring the quality of the
products.
3. General considerations
The quality, safety and efficacy of a biological product are the prime
responsibility of the manufacturer; however, the national health authority
of each Member State is responsible for establishing procedures for
assuring that biological products intended for use in the country are of
adequate quality, safety and efficacy. This responsibihty should have a firm
statutory basis backed by legislation. Marketing approval for a biological
product should be granted by a national control authority (NCA), which
should also be responsible for continued post-marketing monitoring. In
carrying out these activities, the NCA should make use of expert
committees and t echcal advisers, and have access to laboratory
facilities.'
Individual Member States should have written standards, both general and
product-specific, for biological products available for use in their
countries. These should be based on contemporary standards, such as
those available from WHO, and harmonized as far as possible with those
of other Member States. For newly developed products, WHO, national
and pharmacopoeia1 requirements may not have been developed and the
NCA will need to agree on specifications with the manufacturer on a
case-by-case basis.
In countries where biological products are manufactured, the NCA should
have appropriate expertise to evaluate the adequacy of the manufacturer's
establishment and facilities, starting materials, production processes,
control-test procedures and product specifications, to determine whether
they meet international and/or national requirements. These control
activities should be fully independent of those of the manufacturer; ideally
the national laboratory facilities should form a single administrative unit
designated as the national control laboratory (NCL). The NCL may be
administered directly by, or on behalf of, the NCA.
In countries where biological products are not manufactured, alternative
approaches may be acceptable for assuring the safety and efficacy of these
products (see section 8). However, an approval process h t e d to a mere
listing of facilities and products would not be considered adequate.
In view of the complexity and cost of certain resources needed for control
testing, it may be unavoidable in certain cases to share such resources with
the manufacturer or an academic institution, or to rely on the resources of
an NCL in another Member State.
National control authorities should, whenever appropriate, exchange
information on safety issues, within the constraints of confidentiality, in
accordance with the WHO Certification Scheme on the Quality of
Pharmaceutical Products Moving in International Commerce (4).
In this document reference is made only to the role of the NCA with respect to biologicals; in
practice it is to be expected that the NCA will have responsibility for all pharmaceutical
products.
Structure of a national control authority for biological products
In countries where biological products are manufactured, the health
authorities should establish and maintain a competent NCA and NCL.
It is recommended that the NCA should make use of independent
expert advisers and advisory committees with appropriate expertise and
have access to testing facilities, such as those of the NCL, to support
decision-making. In some instances a multinational or regional structure
may be more efficient.
Personnel
The personnel of the NCA and the NCL should include person(s)
qualified and experienced in the control of biological products and experts
in all appropriate disciplines. The qualifications and experience of the staff
at all levels should be appropriate to the review and control activities
required for the range of biological products to be controlled. It is
advantageous for the director of the NCL to report directly to the director
of the NCA.
Contact between NCA and NCL personnel and scientists working in
related fields will be beneficial for exchanging ideas and discussing
techniques, problems and analytical results.
All staff of the NCA and NCL should receive suitable training through
active training programmes, covering both the technical and the
administrative aspects of control procedures.
Encouragement of research activities within the NCL will both lead to the
development of better control methods and help the laboratory to retain an
interested, efficient and highly qualified staff.
Administration
The NCA should have established procedures for the receipt and review of
manufacturers' submissions and for testing samples provided in support of
applications. On completion of the review procedures, which include the
evaluation of detailed reports (see sections 5 and 6), the NCA issues a
notice of approval or disapproval to the manufacturer. It may also issue
notices of suspension or revocation of approval. Consideration should be
given to making available appropriate legal expertise in support of this
activity.
The NCA should maintain adequate filing and archiving facilities, such
that all submissions, evaluations, records and correspondence are
available and kept up to date. Attention should be given to the need to
maintain commercial confidentiality.
The NCA and NCL should possess, or have access to, library facilities
appropriate to their fields of activity. The documents available should
include: current national and international requirements for products that
are manufactmed locally, relevant international requirements for
biological substances, and other relevant specifications and recommen-
dations published by WHO or other bodies.
4.3 Good manufacturing practices (GMP) inspectorate
The NCA should have access to suitably qualified inspectors who are
independent of manufacturers. The purpose of inspections will be to
ensure compliance of each manufacturer's facilities and procedures with
the principles of GMP as described in WHO publications (5, 6) and with
the requirements and/or conditions for the approval for the product
concerned. Guidelines are available for conducting inspections of
manufacturers of both drugs and biologicals (7). Reciprocal arrangements
for international inspection such as those of the Pharmaceutical Inspection
Convention of the European Free Trade Association (8) may be used, as
may the WHO Certification Scheme on the Quality of Pharmaceutical
Products Moving in International Commerce (4).
5. Procedures for approval of manufacturers and products
Approval or licensing of a manufacturing establishment for production of
biologcal products should be granted only if the manufacturer complies
with the principles of GMP (5, 6), as confirmed by inspection.
Approval or licensure of a given biological product will be given by the
NCA when it is satisfied that the product conforms to the relevant national
and/or international requirements, including the manufacturer's specifi-
cations applicable to the product. In order to evaluate the safety and
efficacy of a biological product, the NCA should review the following
detailed information before granting an approval.
5.1 Information on the manufacturing establishment
The manufacturer should provide sufficient information to demonstrate
compliance with the principles of GMP (5, 6), including the existence of
adequate quality-assurance systems. Plans, diagrams, flow charts and texts
may be used to convey the necessary information in relation to (but not
limited to):
personnel:
- qualifications and experience,
- organization and reporting relationships,
- training schedules and recording systems;
location and construction of the buildings used for manufacture and
control;
flow of raw materials, personnel and manufactured product through the
facility;
animal facilities;
air, water and steam systems and power supply;
drainage and effluent systems;
segregation of operations;
lists of major equipment;
maintenance schedules for equipment and building services;
cleaning schedules;
quality-assurance and quality-control procedures;
storage and quarantine facilities and procedures for:
- raw materials,
- packaging materials,
- in-process and bulk materials,
- final product;
validation procedures;
documentation and record-keeping systems;
labelling and packaging facilities and procedures;
recall and retrieval procedures.
To be certain that the buildings, facilities, personnel, procedures and
practices comply with the description in the licence application, the NCA
should arrange for the inspection of the manufacturer before granting the
licence. The inspector(s) selected should be independent of the
manufacturer and have sufficient expertise to conduct a meaningful review,
in accordance with section 4.3, of the GMP system in use (including
buildings, facilities, procedures, personnel and quality assurance).
5.2 Information on the product
The manufacturer should provide sufficient information to demonstrate
the safety and efficacy of the product as manufactured and controlled in
the establishment described above. The NCA should request from the
manufacturer a critical evaluation of the procedures adopted for
manufacture and control of the product and of preclinical and clinical
studies relevant to its proposed use. The submission should include the
following details, if appropriate:
source materials (e.g. microorganisms, blood/plasma donations,
cells/cell substrates, pollen), including their specifications and the tests
used to demonstrate compliance with the specifications;
raw materials and packaging materials, including their specifications
and the tests used to demonstrate compliance;
methods of manufacture, including a description of seed-lot and
cell-substrate systems used, together with in-process, bulk and final
product specifications and the tests employed to demonstrate
compliance;
demonstration of consistency of manufacture, which normally
comprises the results of tests on a minimum of three satisfactory and
consecutive production batches of a size corresponding to that
contemplated for routine production;
any proposal for reprocessing of the product;
stability studies undertaken to justify the proposed validity period for
the product under the indicated storage conditions;
labels and package inserts;
documentation used in the manufacturing and control procedures,
including standard operating procedures and protocols containing
details of production and quality-control testing;
reports of preclinical studies;
clinical trial data;
a list of countries in which the product is approved for use.
The nature and extent of pre-licensing testing undertaken by the NCA
should reflect any particular quality-assurance considerations relevant to
the product; as a minimum, the NCA should undertake tests to evaluate its
safety and efficacy. It may also perform chemical, physical and biological
tests additional to those specified in national or international
requirements.
The national control laboratory
The size of facilities and number of staff of the NCL udl depend on the
nature and extent of the quality control required. Some guidance is
available in the Manual for the design, equipping and stnfSing offacilities for
production and quality control of bacterial vaccines (9).
Laboratory testing and evaluation
The NCL (or equivalent) should be able to perform all necessary tests on
samples of source materials and of intermediate, bulk and finished
products. This will require specialized facihties and equipment. If the NCL
is on a site where biological products are manufactured, national control
activities should be independent of control activities associated with
manufacture or production.
The NCL's responsibilities should include some or all of the following
activities:
provision of advice to the NCA on technical matters relevant to the
approval of products and manufacturing establishments;
evaluation of manufacturers' preparative and analytical procedures,
standard operating procedures: validation experiments and batch
protocols;
pre-licensing control testing of samples of batches, in particular for
ascertaining consistency of production, as well as testing for batch
release;
evaluation of shelf-life specifications and expiry dates of final lots on
the basis of the manufacturer's thermal stability tests and stated
conditions of storage, and experimental verification of stability;
development, evaluation: establishment and implementation of testing
procedures and release criteria;
review of reports of quality defects in distributed material, retesting if
appropriate, and provision of advice on whether the preparations
should remain on the market or be withdrawn;
undertaking of research in relation to the above activities (which may
involve collaboration with manufacturers).
In order to fulfil its responsibilities, the NCL should have the authority to
demand appropriate samples (e.g. of starting materials, intermediate
products and finished biologicals) from manufacturers. The samples
should be properly labelled and portions should be kept for future
reference.
The control laboratory should maintain adequate analytical records of all
samples examined, including:
the results of tests performed, including original observations and
calculations, relating to compliance with the established specifications;
the date and signature(s) of the person(s) who performed the
quality-control tests; and
a final review, with a dated endorsement of the final decision by a
responsible person.
6.2 Establishment of national reference materials for biological substances
WHO has published guidelines on the preparation, characterization and
establishment of international and other reference materials (10), and a list
of International Standards, International Reference Reagents and
International Reference Preparations is available (11).
It may be desirable for appropriate national (secondary) reference
materials, calibrated against international reference materials, to be
established by the NCL and made available to manufacturers. However, a
multinational or regional approach to the establishment and supply of
secondary reference materials may be more efficient. The secondary
reference materials should be used in the routine laboratory testing of
biological products. Their use permits the expression of potency in
International Units, and in some cases they may be useful in confirming the
identity of biological products.
6.3 Other activities of the national control laboratory
The NCL, or the laboratories providing the services of an NCL, should
devise effective internal control measures to permit the evaluation of their
reliability in performing all tests. The inclusion of reference preparations
and coded replicate samples in test procedures, simultaneous independent
testing, and routine checks on the sensitivity and calibration of instruments
are necessary as part of good laboratory practice for the NCL. The NCL
should, if possible, participate in collaborative studies with other NCLs
and other relevant laboratories to enhance its expertise.
7. Post-licensing monitoring of products
7.1 Product release
At the time a product is approved, the NCA should decide whether
controls involving the NCA are to be applied to release of batches of the
product. Ths decision will be influenced by the nature of the product.
Controls will usually be imposed on complex products and on those
obtained by complex manufacturing procedures. The control system may
involve the following activities and may be reviewed and revised once
satisfactory and consistent production has been demonstrated:
7.1.1 Testing of samples of intermediate, bulk or final product, to confirm
compliance with the requirements and agreed specifications. The nature
and frequency of the tests to be carried out are decided by the NCA.
7.1.2 Evaluation of the manufacturer's protocols for manufacture and
control of each batch. Examples of model summary protocols are annexed
to the individual Requirements for Biological Substances published by
WHO. The critical review of batch protocols by the NCA is a most
important part of the control of biological products. The information
provided should make it possible to review the manufacture and testing of
each batch of a particular product, including all required in-process
controls and control tests on final products, to confirm compliance with
the approved specifications.
7.2 Inspections
Periodic inspections of the manufacturing facihty should be carried out on
behalf of the NCA to assure continued compliance with GIMP and with the
specifications established for the product at the time of approval. Records
of complaints and reports of adverse reactions should be examined.
7.3 Post-marketing surveillance
The procedures described in sections 7.1 and 7.2 above do not preclude
the need for a post-marketing sampling and surveillance system. Countries
should establish a national system for the post-marketing surveillance of
biological products. Clinicians and other health workers should be
encouraged to report to manufacturers and NCAs unexpected adverse
events occurring after administration of biological products. The
manufacturers and the NCAs should assess these reports and, in
consultation with each othel; attempt to evaluate their significance. Ths
assessment may require the testing of products already released and
inspection of production and control facilities. If an imported product is
associated with adverse reactions, the manufacturer and, where
appropriate, other NCAs and WHO should be notified.
Guidance for operating a monitoring system for adverse reactions is
provided in a report published by the Council for International
Organizations of Medical Sciences (12).
Recall and revocation
NCAs should have a system for enforcing the recall of batches, revoking
approvals, and communicating such decisions to users and to the NCAs of
any countries importing the product.
Approval of manufacturing changes
Any significant change to the manufacturing establishment, source
materials, production process, quality-assurance procedures, product
specifications or labelling should have the prior approval of the NCA.
Approval of new indications
NCAs should require that significant proposed changes in product
indications or use be submitted by manufacturers for evaluation and
approval.
Procedures for approval of imported products
The national authorities of countries wishing to import biological products
could simplify the licensing formalities, and reduce the need for testing, by
accepting certificates, issued by the responsible authorities in the country
of manufacture, stating that the quality of the product meets a certain
standard. The WHO Certification Scheme on the Quality of
Pharmaceutical Products Moving in International Commerce (4) and
GMP texts (5, 6), with the inclusion of the procedures described in t hs
section, provide a suitable basis for such a mechanism. For the purpose of
this Certification Scheme, "biological product" refers to a product
presented in its finished dosage form and to the bulk material that is
processed to produce this dosage form.
Participating Member States
Each Member State participating in the Certification Scheme should
communicate to WHO the name and address of the department of its NCA
dealing with biological products and, if appropriate, any significant
reservations relating to its participation. WHO would then notify all other
Member States.
Exporting Member States participating in the Certification Scheme should
ensure that:
approval of biological products is subject to appropriate control testing
by the NCA to assure safety and eficacy, and adequate facilities are
available for such testing;
the manufacturer conforms to requirements for GMP and quality
assurance of biological products as recommended by WHO, or to
equivalent national standards;
the NCA conducts appropriate inspections, including, for example,
examination of records and samples, to ensure that manufacturers
conform to these requirements;
the inspectors in the service of the NCA have appropriate expertise.
Exporting Member States participating in the Certification Scheme
should, whenever possible, ensure that International Nonproprietary
Names (INN) are used on certificates and for labelling the biological
product.
8.2 Certification of products
Biological products exported under the Certification Scheme should be
certified by the NCA of the exporting Member State by means of
certificates to be sent to the NCA of the importing Member State. The
importing Member State would then either License the product or make
licensing conditional on the submission, and approval, of supplementary
data.
The issue of certificates for a biological product would be subject to the
conditions set by the NCA of the exporting Member State. Certificates
would, however, be expected to state that:
- the product is approved for use within the exporting Member State (if
not, the reason should be given); and
- the manufacturing establishment in which the product is produced is
inspected at suitable intervals to check that the manufacturer conforms
to the principles of GMP (5, 6) and quality assurance (as defined in the
present guidelines).
For many biological products, certification on an individual lot basis is
necessary because of the difficulty of controlling starting materials and
ensuring that batch-to-batch variation is within acceptable h i t s .
Suggested model certificates for biological products are given in
Appendices 1 and 2.
8.3 Requests for additional information
Additional information may be requested by the NCA of the importing
Member State from the NCA of the exporting Member State. This
information maj7 be provided directly by the NCA, or through the
manufacturer, and may include:
details of the implementation of requirements for GMP and quality
assurance of biological products;
information on control tests performed on the product by the NCA of
the exporting Member State;
the names and functions of the persons officially designated to sign
release certificates for individual batches of the product;
copies of all documentation and labels that are supplied with the
product on packaging materials and package inserts and that have been
approved by the NCA in the exporting Member State, together with the
date(s) on which such approval was accorded.
information on general and specific standards for quality assurance of the
biological product to be exported may also be requested if so required by
the legislative provisions of the importing Member State. The consent of
the manufacturer to the provision of such information should be obtained
by the NCA of the exporting Member State.
8.4 Reporting of defects and adverse reactions
Defects may occur in the quality of biological products imported under
the Certification Scheme. If they are considered to be of a serious nature
by the importing country, and are not attributable to local conditions of
storage and transport, the NCA of the importing country should notify the
NCA of the exporting Member State and provide the relevant data.
Adverse reactions of unexpected severity or frequency should also be
notified to the NCA of the exporting country. Similarly, if the NCA of the
exporting Member State discovers quality defects or receives reports of
unexpected adverse reactions, it should inform the NCA of the importing
Member State of any action taken.
8.5 Procedure for testing imported biological products
Countries wishing not to rely solely on the certification scheme described
in sections 8.1-8.4 may consider implementing an abridged version of the
system of control applicable to the NCA of the country of manufacture, as
described in sections 4-7. The system may include a review of information
on the manufacturing establishment (as described in section 5.1) and on
the biological product to be imported (as outlined in section 5.2), in order
to assess its safety and efficacy. If adequate facilities and personnel of
appropriate expertise are available, pre-licensing testing may be
performed as described in section 7.1.1, although intermediate samples
may not be available. Additionally, the NCA of the importing country may,
if necessary, perform control tests on the biological product on a
batch-to-batch basis, to obtain assurance regarding safety and efficacy,
including the possibility of defects occurring during shipment.
Authors
The draft text of these guidelines was prepared at a meeting of a WHO Ad Hoc
Committee on Guidelines for National Authorities and Manufacturers on Quality
Assurance for Biological Products, held in Ottawa, Canada, 11-15 June 1990,
supported by the Health Protection Branch, Bureau of Biologics, Ottawa, and attended
by the following participants:
Dr J. Ayres, Group Director, Quality Assurance, Wellcome Foundation Ltd., Dartford,
Kent, England
Dr A. Benmansour, Laboratory of Viral Genetics, National Centre for Scientific
Research, Gif-sur-Yvette, France
Dr A. Breschkin, Chief, Virology Section, Therapeutic Goods Administration
Laboratories, Parkville, Australia
Dr Darodjatun, President Director, Perum Bio Farma, Bandung, Indonesia
Dr S. G. Drozdov, Director, Institute of Poliomyelitis and Viral Encephalitides, Moscow,
USSR
Dr E. Esber, Associate Director for Research and Regulatory Coordination, Center for
Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD,
USA (Chairwoman)
Dr J. Furesz, Director, Bureau of Biologics, Ottawa, Ontario, Canada
Dr A. Homma, Oswaldo Cruz FoundationIMinistry of Health, Manguinhos, Rio de
Janeiro, Brazil
Dr S. Jeffcoate, National lnstitute for Biological Standards and Control, Potters Bar,
Herts., England (Rapporteur)
Dr V. R. Kalyanaraman, Director, Pasteur lnstitute of India, Coonoor, India
Mrs S. F. Langlois! Director, Regulatory Affairs, Connaught Laboratories Ltd., A Pasteur
Merieux Company, Willowdale, Ontario, Canada
Dr D. Magrath, Chief, Biologicals, WHO, Geneva, Switzerland
MS C. Moor, Cutter Biological/Miles Inc., Berkeley, CA, USA
Dr J. Obijeski, Genentech Inc., South San Francisco, CA, USA
Dr P. Sizaret, Scientist, Biologicals, WHO, Geneva, Switzerland
Dr J.-M. Spieser, European Pharmacopoeia Commission, Council of Europe,
Strasbourg, France
Mr J. C. Weber, Wymbolwood Beach, Wyevale, Ontario, Canada
Dr Xiang Jianzhi, Head, Division of Science & Technology, Shanghai lnstitute of
Biological Products, Shanghai (Western), People's Republic of China
Acknowledgements
Acknowledgements are due to the following experts for their comments and advice:
Dr J. Cameron, North York, Ontario, Canada; Dr A. Fenyves, Paul Ehrlich Institute,
Langen, Germany; Dr C.Guthrie, General Manager, Blood Products Division, CSL
Ltd., Parkville, Australia; Dr M. Kantoch, Head, Virology Department, National lnstitute
of Hygiene, Warsaw, Poland; Mr J. Lyng, State Serum Institute, Copenhagen,
Denmark; Dr N.V.Medunitsin, Director, Tarasevich State lnstitute for the
Standardization and Control of Medical Biological Preparations, Moscow, USSR.
References
1. WHO Expert Committee on Biological Standardization. Forty-second Report.
Geneva, World Health Organization, 1992 (WHO Technical Report Series,
No. 822) Annex 7.
2. The national control of vaccines and sera. (A guide to the provision of technical
facilities.) In: WHO Expert Committee on Biological Standardization. Thirty-first
Report. Geneva, World Health Organization, 1981 (WHO Technical Report Series,
No. 658), Annex 11.
3. General Requirements for Manufacturing Establishments and Control
Laboratories (Requirements for Biological Substances No.1). In: Requirements
for Biological Substances. Report of a WHO Expert Group. Geneva, World
Health Organization, 1966 (WHO Technical Report Series, No. 323), Annex 1.
4. WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in
International Commerce. In: WHO Expert Committee on Specifications for
Pharmaceutical Preparations. Thirty-first Report Geneva, World Health
Organization, 1990 (WHO Technical Report Series: No.790), Annex 5.
5. Good manufacturing practices for pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations. Thirty-second
Report. Geneva, World Health Organization, 1992 (WHO Technical Report
Series, No. 823); Annex 1.
6. Good manufacturing practices for biological products. In: WHO Expert
Committee on Biological Standardization. Forty-second Report. Geneva, World
Health Organization, 1992 (WHO Technical Report Series, No. 822), Annex 1.
7. Guidelines on inspection of pharmaceutical manufacturers. Geneva, World
Health Organization, 1990 (unpublished document WHOlPHARMl90.133;
available on request from the Division of Drug Management and Policies,
World Health Organization, 1211 Geneva 27, Switzerland).
8. Convention for the mutual recognition of inspection in respect to the
manufacture of pharmaceutical products, 1970. Geneva, European Free Trade
Association.
9. Manual for the design, equipping and staffing of facilities for production and
quality control of bacterial vaccines. Geneva, World Health Organization, 1978
(unpublished document BLG/UNDP/78.1; available on request from Biologicals,
World Health Organization, 1211 Geneva 27, Switzerland).
10. Guidelines for the preparation, characterization and establishment of
international and other standards and reference reagents for biological
substances (revised 1989). In: WHO Expert Committee on Biological
Standardization. Fortieth Report. Geneva, World Health Organization, 1990
(WHO Technical Report Series No. BOO), Annex 4.
11. Biological substances: lnternational Standards and Reference Reagents 1990.
Geneva, World Health Organization, 1991.
12. lnternational reporting of adverse drug reactions. Final report of the ClOMS
Working Group. Geneva, Council for International Organizations of Medical
Sciences. 1990.
Appendix 1
Model certificate of approval of a biological
product
Name and dosage form of product:
Manufacturer and/or, when applicable, person responsible for placing the
product on the market:
It is certified that:
U This product has been authorized to be placed on the market for use in
t hs ~ount r y. ~
Number of licence and date of issue (if applicable):'
The enclosed documents constitute the complete text of all labelling
and prescribing information authorized for use in this country.'
or
This product has not been authorized to be placed on the market for use
in this country for the following reasons:
p- -
It is also certified that (a) the manufacturing plant in which the product is
produced is subject to inspections at suitable intervals, and (b) the
manufacturer conforms to requirements for good manufacturing
practices
3
and other relevant requirements published by WHO, in respect
of products to be sold or distributed withn the country of origin or to be
exported.
Name of designated authorized person (typed)
(Signature of designated authorized person) (Place and date)
l This certificate is intended to define the status of the biological product and its manufacturer in the exporting
and manufacturing country. it is issued by the competent national authority in the exporting country ~n
response to a request by the cornpeteni national authority in the importing country. It may be required by the
importing country at the time of the first importation and subsequently if confirmation or updating is
required. The certificate is intended to be product-specific, since confusion will inevitably arise if information
relating to different products, or even different dosage forms of the same product, is attached to the same
certificate; whenever possible, International Nonproprietary Names (INN) or national nonproprietary names
should be used.
Deiete as approxiate.
Good msnufacturing practices for pharmaceutical products. In: WHO Experr Committee on Specifications
for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992 (WHO
Technical Report Series, No.823), Annex 1 ; Good manufacturing practices for biological products. In:
WHO Expert Committee on Biologicai Standardization. Forty-second Report. Geneva, World Health
Organ~zation, 1992 (WHO Technical Report Series? No.822), Annex 1.
Appendix 2
Model certificate for the release of a lot or lots of
a biological product
The following biological product , produced by 1
in ,2 whose lot numbers appear on the labels of the final
containers, meets all national requirements (
3,
and is manufactured in accordance with the requirements for good
manufacturing practices
4
and (if applicable) the product-specific
requirements published by WHO.
Lot number Expiry date
As a minimum this certificate is based on examination of the
manufacturing protocol.
Address of the National Control Authority or Laboratory
Name of the Director of the National Control Authority or Laboratory
(or representative)
Signature
Date
Name of manufacturer.
Country.
Reference to appropriate document.
Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health
Organization, 1992 (WHO Technical Report Series, No.823), Annex l ; Good manufacturing
practices for biological products. In: WHO Expert Committee on Biological Standardization.
Forty-second Report. Geneva, World Health Organization, 1992 (WHO Technical Report
Series, No. 822), Annex 1.
O World Health Organization
WHO Technical Report Series, No. 822, 1992
Annex 3
Guidelines for assuring the quality of
monoclonal antibodies for use in humans
Introduction
Scope
General considerations
Part A. Manufacturing guidelines
A.l Definitions
A.2 Reference materials
A.3 General manufacturing requirements
A.4 Production control
A.5 Distribution and shipping
A.6 Stability test and validity period
Part B. National control guidelines
B. l General
B.2 Release certification
Authors
Acknowledgements
References
Appendix 1
Possible viral contaminants in hybridomas of murine origin
Appendix 2
Human tissues that should be considered for immunohistochemical
investigations of the reactivity of monoclonal antibodies
Appendix 3
Model certificate for the release of monoclonal antibodies
Introduction
Unlike conventional polyclonal antibodies, monoclonal antibodies are
homogenous products secreted by immortalized B lymphocytes that are
cloned and expanded in continuous cell lines. Such cell lines may be
cultivated for the stable secretion in large quantities of antibodies of
defined specificities. Monoclonal antibodies produced in this way are
available for a variety of clinical purposes such as anti-tumour therapy,
immunomodulation (e.g. to prevent graft rejection) and passive
immunization, as well as for in vivo diagnosis and preparative procedures
for the manufacture of biologicals. They are currently obtained from
murine or human cells.
Murine monoclonal antibodies are obtained from murine hybridomas
produced by fusion of B lymphocytes from immunized mice or rats with
murine myeloma cells.
For human monoclonal antibodies, a major difficulty has been the
generation of human hybridoma cell lines of acceptable stability. It is also
difficult in most cases to obtain antigen-primed human B lymphocytes
suitable for fusion. In view of this, several alternative strategies have been
devised for the production of human monoclonal antibodies. They
include:
- fusion of human B lymphocytes with a murine myeloma or hybrid
human-murine myeloma cell line;
- fusion of human B lymphocytes with a human lymphoblastoid cell line;
- transformation of human B lymphocytes with Epstein-Barr virus
(EBV; human (gamma) herpesvirus 4);
- fusion of an EBV-transformed human B-lymphocyte line with a mouse
myeloma cell line.
Scope
The requirements set out below are intended to apply to murine and
human monoclonal antibodies for use in humans, including in vivo
diagnosis and ex vivo (extracorporeal) treatment. It is recommended that
monoclonal antibodies intended for use in the preparation of biological
products to be used in humans should also meet these requirements,
except for those relating to the final product (section A.4.5); however,
validation of the purification process employed after the step when
monoclonal antibodies are used during preparation of the biological
product may diminish this need. This document is not concerned with the
production of monoclonal antibodies by recombinant DNA techniques,
such as "humanized antibodies, nor with monoclonal antibodies to be
used for in vitro diagnostic purposes.
General considerations
An important consideration for the clinical use of monoclonal antibodies
is that of potential microbial contamination, especially by viruses. While
murine cells can harbour a range of viruses, murine hybridoma cells
usually contain only A-type and C-type endogenous retroviruses, whch
are thought unlikely to be pathogenic for humans. A cell line that expressed
any virus capable of infecting human cells would be acceptable only in
exceptional circumstances for use in preparing monoclonal antibodies.
Other important considerations for the clinical use of monoclonal
antibodies relate to the presence of potentially oncogenic residual cellular
DNA, the possible undesired immunological reaction of the antibody with
human tissues, and the induction of antibodies in the recipient against
imrnunoglobulins or other proteins present in the product. Antibodies
induced in the recipient may result in adverse reactions and limit the
duration of effective therapy. It is, in any case, desirable to minimize the
quantity of heterologous protein contaminants administered to the patient,
for example by using for fusion purposes a parental myeloma cell that does
not synthesize immunoglobulins.
Each of the following sections constitutes a recommendation. The parts of
each section that are printed in type of normal size have been written in the
form of requirements, so that, if a health administration so desires, these
parts as they appear may be used as definitive national requirements. The
parts of each section that are printed in small type are comments and
recommendations for guidance.
Should individual countries wish to adopt these guidehes as the basis of
their national regulations concerning monoclonal antibodies, it is
recommended that modifications be made only on condition that they are
shown to ensure at least an equal degree of safety and potency of the
product. The World Health Organization should be kept informed of the
action taken.
While the guidelines set out below should be considered generally
applicable, individual products may present particular quality-control
problems. The production and quality control of each product must
therefore be given careful individual consideration, any special features
being taken fully into account. Furthermore, the guidelines for a product
must reflect its intended clinical use. Different requirements might
justifiably apply, for example, to a product to be used in a life-threatening
condition.
Part A. Manufacturing guidelines
A.I Definitions
A.1 .l International name and proper name
The international name of products shall be the officially assigned
nonproprietary or generic name; the proper name shall be the translation
of the international name in the language of the country of origin, followed
by the designation of the immunological specificity. The name shall be
restricted to preparations that satisfy the requirements formulated below.
A.1.2 Descriptive definition
A.1.2.1 Murine monoclonal antibodies
Murine monoclonal antibodies are antibodies obtained from murine
hybridomas produced by fusion of B lymphocytes from immunized mice
or rats with murine myeloma cells.
A.1.2.2 Human monoclonal antibodies
Human monoclonal antibodies are antibodies produced by human B
lymphocytes immortalized through transformation with EBV or other
techniques.
A.1.3 Terminology
A.1.3.1 Animals
Murine: Belonging to the Muridae family, which includes mice and rats.
A.1.3.2 Seed lot system
Original cell line: The cell line produced or acquired by the manufacturer,
on which the production of the master cell bank is based. The history of the
original cell line (including details of parent cells, immunogens and fusion
or immortalization methods) should be recorded whenever available.
Master cell bank: Homogeneous cell suspension derived from the original
cell line. It is stored frozen in the vapour phase above liquid nitrogen in
aliquots of uniform composition, one or more of which are used for the
production of the manufacturer's working cell bank.
Manufacturer's working cell bank (MWCB): A quantity of cells of uniform
composition, derived from one or more containers of the master cell bank
and stored frozen in the vapour phase above liquid nitrogen in aliquots,
one or more of which are used for production purposes.
A.1.3.3 Methods of production
In vivo production: Method based on the injection into the peritonea1
cavity of mice or rats of cells derived from the MWCB by in vitro cell
culture. After a suitable incubation period, ascitic fluids are harvested by
abdominal puncture. The procedure used to collect ascitic fluid should be
adequately described in a standard operating procedure.
In vitro production:
(a) Batch system: Method of production in which the cell-culture fluid(s)
from the production vessel(s) idare harvested on a single occasion. The
maximum number of passages or population doublings of cells of the
MWCB is approved by the licensing authority.
(b) Continuo~ls cell-czdtwe system: Method of production in which the
cell-culture fluid(s) from the vessel(s) used for the last passage idare
harvested on multiple occasions. The maximum number of passages or
population doublings, the maximum incubation period for the last
passage, and the maximum number of single harvests are approved by the
licensing authority.
A.1.3.4 Production stages
Single hm-vest: Filtrate obtained from one batch of cell cultures seeded (in
vivo or in vitro), incubated and harvested together.
B~dk harvest: Homogeneous pool of single harvests (e.g. filtrates of ascitic
fluids or of supernatants of cell cultures) that are processed together in a
single manufacturing run.
Purified bulk: Product after purification of a bulk harvest is complete. It is
used in the preparation of the final bulk.
Final bulk: The homogeneous preparation present in a single container
from which the final containers are filled either directly or through one or
more intermediate containers.
Finalproduct: Finished product that is formulated and dispensed into final,
sealed containers which hold the liquid or freeze-dried product in its final
dosage form.
Final lot: A collection of sealed final containers that have been filled from a
single container in a single continuous working session, are uniform in
their contents, and are homogeneous with respect to the risks of
contamination during filling and freeze-drying.
A. 1.3.5 Adventitious agents
Contaminating microorganisms of cell cultures or ascitic fluids: including
bacteria, fungi, mycoplasmas and viruses.
A.2 Reference materials
Part of a lot that has been fully characterized and evaluated in studies in
humans shall be kept as an "in-house" reference material under conditions
that maintain its stabihty for use in assays of subsequent lots; this is of
particular importance if international reference materials are not available.
The criteria for establishing manufacturers' reference materials shall be
approved by the national control authority.
In cases where monoclonal antibody preparations have a short validity period
(e.g. certain radiolabelled monoclonal antibodies), the reference material may
consist of an unlabelled immunoglobulin material.
A.3 General manufacturing requirements
Manufacturing and control methods shall comply with "Good
manufacturing practices for pharmaceutical products" (l), "Good
manufacturing practices for biological products" (2) and the revised
Requirements for Biological Substances No. 27 (Requirements for the
Collection, Processing, and Quality Control of Blood, Blood Compo-
nents, and Plasma Derivatives) (3).
A.3.1 General procedure(s) for generating hybridomas and producing
monoclonal antibodies
Methods used for lymphocyte isolation, fusion of myeloma cells and
lymphocytes, immortalization of lymphocytes, selection of hybridomas
and screening of antibodies shall be recorded.
A.3.1.1 Material used for immunization
The material used for the generation of immune lymphocytes should be
defined. If the immunogen is derived from a human source, relevant
clinical data on the donor should be recorded.
A.3.1.2 Immune parental cells
Wherever possible, the source of the immune parental cells shall be
documented. For murine monoclonal antibodies, information on the
animal strain shall be provided, including its specific-pathogen-free (SPF)
status; the animals used for immunization should, whenever possible, be
SPF.
In the case of human monoclonal antibodies, all data relevant to possible
viral infections of the human donors of the immune parental cells should
be available. The donations employed should be screened for potential
viral contamination, as a minimum in accordance with current require-
ments for blood donations (3).
A.3.1.3 lmmortalization procedures
If myeloma cells are used, they should be fully described, with details
including their source, name and characteristics.
Human B lymphocytes are usually immortalized by infecting them with EBV;
however, this procedure alone cannot always ensure stability, and subsequent
fusion with a myeloma may be required.
If EBV is used for immortalizing human B lymphocytes, its origin and
characteristics should be clearly specified.
It is preferable to use immortalizing cells that do not synthesize immuno-
globulins.
Test for bacteria, fiingi and mycoplasmas. Before being fused or
immortalized, cells should be tested according to the revised
Requirements for Biological Substances No. 6 (General Requirements for
the Sterihty of Biological Substances) (4) or by a method approved by the
national control authority, and should be found negative for bacterial,
fungal and mycoplasmal contamination.
A. 3. 2 Seed lot system
The manufacture of monoclonal antibodies shall be based on a seed
lot system, which should be described in detail. Information on the
establishment, characterization and cloning of the original cell line used to
establish the master cell bank shall be provided. If feeder layers are used,
their origin and the SPF status of the source animals should be recorded.
A. 3. 3 Master cell bank
The following tests shall be performed on the master cell bank.
A.3.3.1 Identity test for the product
The immunological specificity of the monoclonal antibody derived from
the master cell bank, i.e. its capacity to react with the target antigen and its
isotype and Light-chain composition, shall be established.
A. 3.3.2 Tests for bacteria, fungi and mycoplasmas
The master cell bank shall be tested for bacterial, fungal and mycoplasmal
contaminants as specified in section A.3.1.3.
A.3.3.3 Test for viruses
The master cell bank shall be tested for viral contamination by inoculation
of cell cultures in which a wide range of viruses can be detected; primate
cells shall be included. The cell bank shall also be tested on suckling mice,
adult mice, guinea-pigs and embryonated hens' eggs (5).
Testing in suckling mice may not be feasible when the hybridoma cell line is
extremely tumorigenic in mice,
Other methods, such as those involving immunochemical procedures,
electron microscopy. molecular hybridization, and the polymerase chain
reaction, are also useful for detecting viral contamination.
Appropriate tests should be performed for the presence of non-infectious
complete viral genomes.
A6zo-ine monoclor7al antibodies. The master cell bank shall be tested for the
viruses Listed in Appendix 1 by, for example, the method of antibody
production in mice (MAP) or antibody production in rats (RAP) or a
method of at least equivalent sensitivity.
Tests for murine retroviruses (including the S+L- and XC tests) shall be
carried out.
The master cell bank shall not be used for manufacture if any of the viruses
of Appendix 1, List 1 are found. The presence of other murine viruses does
not automatically preclude use of the cells, provided that adequate
inactivation or removal of these viruses is demonstrated through validation
of the process employed.
Human monoclonal antibodies. Tests on the master cell bank to detect
expression of infectious viruses are of particular importance, especially if
the cells have been transformed by EBV, and should be performed
whenever possible.
The master cell bank should be tested for viral contamination by
inoculation of cells into cultures of virus-free lymphoblastoid cell lines.
The master cell bank shall also be tested with a sensitive marker for the
following viruses: hepatitis B virus, human imrnunodeficiency virus types 1
and 2, human T-cell lymphotropic virus types 1 and 2, human (beta)
herpesvirus 5 (human cytomegalovirus), EBV and human herpesviruses
6 and 7, which may be able to infect, productively or latently, the
lymphocytes used to produce the hybridoma.
The expression of biologically active EBV in the master cell bank may be
acceptable if the production process is shown to remove or inactivate EBV.
Tests to demonstrate the absence of murine viruses shall also be
performed, unless any possible contamination with murine viruses can be
excluded.
A. 3.3.4 Test for undesired immunological reactions
The product derived from the master cell bank shall be tested at least once
to show the absence of undesired reactivity with appropriate tissues, as
listed in Appendix 2.
A.3.4 Manufacturer's working cell bank
If the MWCB is prepared in a manufacturing facility ddTerent from that
where the master cell bank was established, the full testing regime
described in section 3.3 shall be carried out.
It shall be shown to the satisfaction of the national control authority that
the MWCB is stable with respect to its ability to maintain the identity of the
antibody secreted. This stability should be established by studies on
samples of monoclonal antibody from cells cultivated under conditions
that reproduce or mimic the production process, for a number of passages
or population doubhgs approved by the national control authority.
However, when a replacement MWCB is derived from the same master
cell bank as that used for preparing the first MWCB (which has been found
to be satisfactory) and the production conditions have not otherwise
changed, the tests for stability mentioned in the previous paragraph and
the tests mentioned below for identity and absence of viral contaminants
may be omitted.
A.3.4.1 Identity test for the product
The immunological specificity of the monoclonal antibody, i.e. its capacity
to react with the target antigen and its isotype and light-chain compo-
sition, shall be established, except in the case defined at the end of section
A.3.4.
A.3.4.2 Test for bacteria, fungi and mycoplasmas
The MWCB shall be tested for bacterial, fungal and mycoplasmal
contaminants as specified in section A.3.1.3.
A.3.4.3 Viral contaminants
Samples of cells shall be tested for viral contaminants as described in
section A.3.3.3, except in the case defined at the end of section A.3.4.
A. 3. 5 Production processes
All processing of cells shall be done either in an area where no cells other
than those directly required for the process are handled, or under
conditions that prevent cross-contamination.
The production system shall be well defined and documented. For all
production systems it shall be shown that successive cultures or successive
harvests yield identical products. Data provided to the national control
authority for release purposes should include information on yields.
Single harvests shall be obtained aseptically, pooled and purified by
methods described in a standard operating procedure. Criteria for
harvesting, rejecting, terminating and storing cultures shall be defined by
the manufacturer and approved by the national control authority.
Antibiotics of the Plactam type shall not be used at any stage in the
production process.
A.3.5.1 Production from mouse ascitic fluid
If substances other than pristane are used to pretreat mice to facilitate the
growth of hybridomas, they shall be approved by the national control
authority. The mice shall come from SPF-monitored colonies and in
particular shall be free from the viruses mentioned in List 1, Appendix 1. If
mice are found to be contaminated with viruses me,ntioned in List 2,
Appendix 1, the final product may be accepted only if the purification
process is shown to eliminate the Infecting virus(es).
A.3.5.2 Production from in vitro cell cultures
Only cell cultures derived from the MWCB shall be used for production.
Details to be provided to the national control authority include the
cell-culture system used, the cell doubhg time? the number of subcultures,
the duration of subcultivation, the incubation temperature and, in the case
of continuous cell culture, the maximum number of single harvests and the
maximum duration of incubation of the last culture.
If serum is included in the medium used for the production of cell cultures,
it shall be tested to show its freedom from bacteria, fungi, and
mycoplasmas as indicated in section A.3.l.3. Each batch of serum shall be
of certified origin and shall be tested for the absence of viral contaminants.
Test results provided by the supplier of the serum may be sufficient if the
tests are performed according to validated and well documented
procedures. Serum of bovine origin shall come from herds certified by the
appropriate authority to be free from bovine spongiform encephalopathy.
A.3.6 Validation of procedures for purifying monoclonal antibody
The effectiveness of the overall purification process for the monoclonal
antibody shall be demonstrated. The following validation studies shall be
performed in areas other than those dedicated to production.
If a viral genome sequence has been found in the master cell bank, the
product may be used on condition that the purification process is validated
for its capacity to reduce the content of viral subgenomic fragments in the
final product to a level undetectable by hybridization.
A.3.6.1 Validation of procedures for removing contaminating cellular DNA
Until it has been proved that quantities of DNA larger than 100pg per
single human dose do not cause harmful effects, the purification
procedures shall be shown to result in final products whose DNA content
does not exceed that level.
The advantage of using a monoclonal antibody preparation containing more
than 100pg of residual cellular DNA per human dose may sometimes outweigh
the theoretical risk; such situations should be examined by the national control
authority on a case-by-case basis.
When monoclonal antibodies are to be used for long-term treatment, the
risks of repeated exposure to DNA should be balanced against the
beneficial effects of the proposed treatment.
Validation studies for the removal of cellular DNA should be performed
by spiking source materials with known large amounts of representative
DNA. At each purification step, the product should be tested for the
content of DNA. On the basis of the overall reduction obtained in DNA
content (the "reduction factor"), a calculation shall be made of the highest
expected amount of DNA per single human dose (or diagnostic
intervention) in the final product and, in the case of multiple injections, of
the highest expected amount of DNA per full treatment.
A.3.6.2 Validation of procedures for removing viruses
Both the crude material before purification and subsequent fractions
obtained during the various purification stages should be spiked with
appropriate amounts of different viruses. The removal or inactivation of
these test viruses should be determined.
An important part of designing a validation study is determining which
viruses, "relevant" or "model", should be used.
"Relevant" viruses are those that are known, or likely, to contaminate the
source material or products used in the production process. The
purification and/or inactivation process shall be shown to remove or
inactivate such viruses or similar viruses. Cell lines derived from rodents
usually contain endogenous retroviral particles, which may be infectious
(C pal-ticles) or non-infectious (intracisternal A particles); it is therefore
necessary to validate the capacity of the purification process to remove
murine retroviruses from monoclonal antibody preparations obtained
from such cells, for instance by using a murine leukaemia virus. When
human cell lines secreting monoclonal antibodies have been obtained by
immortalization of B lymphocytes by EBV: it is necessary to check the
ability of the purification process to remove EBV by studies with a suitable
herpesvirus.
There may be cases where "relevant" viruses do not have a wide range
of physicochemical properties, or where spiking with "relevant
7
' viruses is
too hazardous; in such cases validation should be performed with "model"
viruses, although the presence of such viruses in cell cultures used for
monoclonal antibody production may be unlikely. Preference should be
given to viruses that display significant resistance to physical and/or
chemical agents. Reduction factors obtained for such viruses provide
useful information on the ability of the production process to remove
and/or inactivate viruses in general. Suitable "model" viruses capable of
resisting a range of physicochemical agents could include:
- SV40 (Polyomavirus maccacae l ), human poliovirus 1 (Sabin) or
another small, non-enveloped virus;
- a parainfluenza or influenza virus and a murine retrovirus (or another
medium-to-large enveloped RNA virus);
- a herpesvirus (e.g. human (alpha) herpesvirus 1 or a pseudorabies
virus) or another medium-to-large DNA virus.
A.3.6.3 Validation of procedures for removing impurities
Additives present in the media (for example sera, serum substitutes, and
substances used for digestion, purification, coupling and increasing
ascitic-fluid production) should be removed during purification. l k s
should be demonstrated by specific validation studies.
~ . 4 Production control
A.4.1 Bulk harvest
Every bulk harvest shall be tested for freedom from bacterial, fungal and
mycoplasmal contamination as specified in section A.3.1.3. Harvests that
are contaminated shall not be used for production.
Every bulk harvest shall be tested on a primate cell line and shown to be
free from detectable viruses.
In addition, every bulk harvest of monoclonal antibodies produced from
ascitic fluid shall be tested for the murine viruses listed in Appendix 1. If
viruses listed in Appendix 1, List 1 are detected, the harvests shall not be
used for production.
A.4.2 Purified bulk
The purified bulk shall pass the tests for absence of bacterial and fungal
contamination as specified in section A.3.1.3. In addition, the following
tests shall be performed on either the purified or the final bulk.
A.4.2.1 Test for components other than those secreted by the cell line or
the hybridoma
A test shall be performed for any auxiliary substance that has been used to
facilitate the growth of the hybridomas or the production of antibodies.
The results shall be shown to be compatible with the maximum amount of
substance per single human dose of the final product as authorized by the
national control authority.
A.4.2.2 Test for residual DNA
A suitable test shall be performed for residual cellular DNA. The result
shall be compatible with the authorized maximum amount per single
human dose of the final product.
A.4.2.3 Test for contaminating viruses
If bulk harvest from mouse ascitic fluid was contaminated with viruses
from List 2, Appendix 1, a test for the absence of such contaminating
viruses shall be performed.
A.4.3 Final bulk
If a preservative is added to the final bulk, its concentration shall have been
shown to have no deleterious effect on the monoclonal antibody and to
cause no unexpected adverse reactions in humans. The preservative and its
concentration shall be approved by the national control authority. Phenol
shaU not be used as a preservative.
The following tests shall be conducted on the final bulk.
A.4.3.1 Test for identity
The monoclonal antibody shall be tested for its isotype composition and
for its immunological reactivity with the target antigen.
A.4.3.2 Test for bacteria and fungi
Each final bulk shall be tested for bacterial and fungal contamination as
specified in section A.3.1.3.
A.4.3.3 Test for purity
The degree of purity of the monoclonal antibodies shall be determined by
chemical and immunological methods. The monoclonal antibodies shall
also be tested for potential contaminants or additives (e.g. leachable
components from chromatography columns, antibiotics, reagents), which
shall not exceed levels approved by the national control authority. The
tests shall include, but not be limited to, the following.
Test for distribzition of molecular size. Generally, not less than 95% of the
immunoglobulin present should be in form of molecular monomers and
dimers. Any departure from this limit requires justification. Separate
additional limits shall be set for the content of dimers, polymers and
fragments.
If the monoclonal antibody is not an imrnunoglobulin G, the test for
distribution of molecular size shall be approved by the national control
authority.
Isoelectric focusing. The product, together with the reference material, shall
be examined by isoelectric focusing; after staining (for example with
silver), the two preparations shall be compared and it shall be
demonstrated that there is no significant difference.
This test may be replaced by chrornatofocusing
Sodium dodecyl sz~lfnte-polyaclylanzide gel electrophoresis (SDS-PAGE).
The product, together with the reference material, shall be examined by
SDS-PAGE under reducing and non-reducing conditions; after staining
(for example with silver), the two preparations shall be compared and it
shall be demonstrated that there is no significant difference.
Test for protein content. The total protein content shall be determined by
ultraviolet spectrophotometry, or any other suitable method.
A.4.4 Filling and containers
The requirements concerning f i h g and containers given in "Good
manufacturing practices for pharmaceutical products" (.l) and "Good
manufacturing practices for biological products" (2) shall apply.
A. 4. 5 Final product
Samples shall be taken from each final product for the following tests.
A.4.5.1 Test for identity
The monoclonal antibody in a labelled container from a labelled final
package shall be tested for both its isotype composition and its
immunologcal reactivity with the target antigen. The result shall meet the
product specification.
A.4.5.2 Test for potency
The biological activity of the monoclonal antibody shall be determined by
either an in vivo or an in vitro test in comparison with the reference
material. The test shall be approved by the national control authority and
the result shall meet the product specification.
A. 4.5.3 Test for pyrogenicity
The product shall be tested for pyrogenicity as described in The
internationalpharmacopoeia (6) or the national pharmacopoeia. The dose
to be injected and the criteria for passing the test shall be approved by the
national control authority.
The national control authority may allow the replacement of the pyrogenicity
test by the LAL (Limulus amoebocyte lysate) endotoxin test after five
consecutive batches have been successfully tested by the two methods.
A.4.5.4 Test for bacteria and fungi
The product shall be tested for bacterial and mycotic contaminants as
specified in section A.3.1.3.
A.4.5.5 Test for abnormal toxicity
Each final lot shall be tested for abnormal toxicity by the intraperitoneal
injection of one human dose, but not more than 1 ml, into each of five mice
(weighing 17-22 g) and injection of not more than 5 m1 into each of two
guinea-pigs (weighing 250-3508). The test shall be approved by the
national control authority. The final product shall be considered
innocuous if the animals survive for at least seven days without showing
signs of abnormal intoxication.
A.4.5.6 Test for protein content
The total protein content shall be determined by ultraviolet spectro-
photometry or another suitable method. Values shall be within limits
that have been shown by the manufacturer to be suitable and have been
approved by the national control authority.
A.4.5.7 Test for residual moisture
If the product is freeze-dried, the average residual moisture in a
representative sample of each final product shall be determined by a
method accepted by the national control authority. Values shall be within
limits that have been shown to be suitable and have been approved by the
national control authority.
A.4.5.8 Test for pH
An appropriate test for pH shall be carried out, if applicable after
reconstitution of the product, and the result shall meet the product
specifications.
The method described in The international pharmacopoeia (6) is suitable for
determining the pH.
A.4.5.9 Test for preservative
If a preservative has been added, its concentration shall be determined and
shown to be in agreement with the value stated on the label, which has been
approved by the national control authority.
A.4.5.10 Inspection of final containers
Each container of each final product shall be inspected visually and those
showing abnormalities of the container or its contents shall be discarded.
A. 4. 6 Records
The requirements given in "Good manufacturing practices for pharma-
ceutical products" (1) shall apply.
A.4.7 Samples
The requirements given in "Good manufacturing practices for pharma-
ceutical products" (1) shall apply.
A. 4. 8 Labelling
The requirements on labels and leaflets given in "Good manufacturing
practices for pharmaceutical products" ( l ) and "Good manufacturing
practices for biological products" (2) shall apply, with the addition of the
following.
The labels on the containers shall include the following information:
- for liquid products: volume and protein concentration;
- for freeze-dried products: protein amount.
The label on the carton or the leaflet accompanying the product shall
include the following information:
- type of source material;
- conditions of temperature recommended during transport and storage.
The statements concerning storage temperature and expiry date appearing
on the label shall be based on experimental evidence and shall be
submitted for approval to the national control authority.
Distribution and shipping
The requirements given in "Good manufacturing practices for pharma-
ceutical products" (1) shall apply.
If the product is to be exported, a copy of the official national release
document (see section B.2) shall be provided by the manufacturer upon
request by the importer.
The purpose of the certificate is to facilitate the exchange of monoclonal
antibody preparations.
Stability test and validity period
A. 6.1 Stability test
Tests shall be conducted before licensing to determine how stable the
product is over the proposed validity period; final containers from at least
three final lots, preferably derived from different bulks and stored under
the conditions recommended to the user, shall be tested for molecular size
distribution, potency, residual moisture, protein content, pH, preservative
and container appearance at the end of the proposed validity period. The
product shall pass these tests.
It is useful to conduct accelerated-degradation tests for these variables on one
or more final lot. A suitable method for conducting such tests on biological
products has been described by Kirkwood (7).
If applicable, the mean percentage loss of potency determined at the end of
the validity period for the three final lots stored under the recommended
conditions shall be compared with t hat hose determined by accelerated-
degradation tests.
A. 6.2 Validity period
The validity period is determined by the results of the stability tests
referred to in section A.6.1.
When changes are made in the production procedure that may affect the
stability of the product, further stability studies shall be conducted to
determine the validity period of the new product. In such a case, the
national control authority may agree to the new validity period being based
on the results of accelerated-degradation tests.
Part B. National control guidelines
6.1 General
The general conditions for national control authorities contained in the
"Guidelines for national authorities on quality assurance for biological
products" ( 8) should apply.
In addition, the national control authority should:
- approve the methods for producing the monoclonal antibody;
- approve the criteria for establishing manufacturers' reference materials;
- approve the tests for extraneous agents and for total protein;
- approve the tests for preservatives and for agents used for purification
or during other stages of manufacture;
- approve the test for distribution of molecular size (if the monoclonal
antibody is not an irnmunoglobulin G);
- approve the tests for determining the potency of the monoclonal
antibody and define the acceptable range of estimated mean values and
the fiducial limits;
- approve the dose to be injected and the criteria for passing the
pyrogenicity test;
- approve the concentration of preservative permitted in the final
product;
- approve the degree of purity of the final product;
- approve the validity period;
- approve the statements concerning storage temperature and expiry
date appearing on the label;
- satisfy itself with the data gathered for ensuring therapeutic effect and
safety in humans.
The national control authority should be satisfied that the results of all
tests, including those done for validating the process of manufacture, are
satisfactory and that consistency of production and testing have been
established.
~ . 2 Release and certification
Monoclonal antibodies shall be released only if they fulfil the requirements
of Part A.
A statement signed by the appropriate official of the national control
authority shall certify whether the final lot of monoclonal antibody in
question meets all national requirements as well as Part A of these
requirements. The certificate shall state the lot number (number appearing
on the labels of the containers), the number under whch the lot was
released and the expiry date. An example of a suitable certificate is given in
Appendix 3. A copy of the official national release document shall be
provided by the national control authority upon request by the
manufacturer.
If the product has a very short validity period (e.g. radiolabelled antibody), a
national certificate may not be required for the release of each final product.
Authors
The first draft of these guidelines was prepared by Dr H. J. M. van de Donk, National
Institute of Public Health and Environmental Protection, Bilthoven, Netherlands, who
acknowledges having consulted for this purpose the following documents:
1. Standard registration document on monoclonal antibodies (National Control
Laboratory, Netherlands, 1988).
2. Points to consider in the manufacture and testing of monoclonal antibody products
for human use (Thomas Hoffman, Chairman, Hybridoma Committee [HFN-8381,
Office of Biologies Research and Review, USA, 1987).
3. Considerations for the standardization and control of the new generation of
biological products (National Institute for Biological Standards and Control,
England).
4. Notes to applicants for marketing authorizations on the production and quality
control of monoclonal antibodies of murine origin intended for use in man
(Committee for Proprietary Medicinal Products, Working Party on Biotechnology
and Pharmacy, Belgium, 1987).
5. Notes to applicants for marketing authorizations on the production and quality
control of human monoclonal antibodies intended for use in man (Committee for
Proprietary Medicinal Products and Biotechnology/Pharmacy, Ad Hoc Working
Party, Belgium, 1990).
The draft was revised at a WHO informal consultation held in Geneva (5-7 February
1991) and attended by the following people:
Mr P. Adamowicz, National Blood Transfusion Centre, Les Ulis, France
Dr T. Bektimirov, Tarasevich State lnstitute for the Standardization and Control of
Medical Biological Preparations, Moscow, USSR ( Vice-chairman)
Dr P. Carthew, Medical Research Council, Carshalton, England
Dr M. Haase, Paul Ehrlich Institute, Langen, Germany
Dr T. Hayakawa, National lnstitute of Hygienic Sciences, Tokyo, Japan
Professor F. Horaud, Pasteur Institute, Paris, France (Chairman)
Dr A. Jouquey, Roussel Uclaf Research Centre, Romainville, France
Dr K. Lambert, Celltech Ltd., Slough, England (CO-Rapporteur)
Dr C. Lucas, TNO Medical Biological Laboratory, Rijswijk, Netherlands
Mr M. Page, Centocor, Malvern, PA, USA
Dr G. Scassellati, Sorin Biomedica S.p.A., Saluggia, ltaly
Dr T. Schreitmiiller, F. Hoffman-La Roche AG, Basel, Switzerland
Dr H. J. M. van de Donk, National lnstitute of Public Health and Environmental
Protection, Bilthoven, Netherlands (CO-Rapporteur)
Professor G. Vicari, lstituto Superiore della Sanita, Rome, ltaly
Dr J. Vincent-Falquet, Pasteur Merieux Sera and Vaccines, Marcy I'Etoile, France
Secretariat (WHO, Geneva, Switzerland)
Dr V. Grachev, Scientist, Biologicals
Dr S. Kopp-Kubel, Pharmaceutical Officer, Pharmaceuticals
Dr D. Magrath, Chief, Biologicals
Dr J. Milstien, Scientist, Biologicals
Dr P. Sizaret, Scientist, Biologicals (Secretary)
Acknowledgements
Acknowledgements are due to the following experts for their comments and advice,
and for supplying additional data relevant to the guidelines: Dr B.Andersson, National
Bacteriological Laboratory, Stockholm, Sweden; Dr E. C. Beuvery, National lnstitute of
Public Health and Environmental Protection, Bilthoven, Netherlands; Dr K. E. Britton,
St Bartholomew's Hospital, London, England; Professor G. L. Buraggi, National
lnstitute for the Study and Treatment of Tumours, Milan, Italy; Professor P. H. Cox,
Dr Daniel den Hoed Clinic, Rotterdam, Netherlands; Dr R. Drost, Centocor, Leiden,
Netherlands; Dr F. Emmrich, Max Planck Institute, Erlangen, Germany; Mr K. Freiling,
Paul Ehrlich Institute, Langen, Germany; Dr J. Furesz, Bureau of Biologics, Ottawa,
Ontario, Canada; Mr C. Guthrie, CSL Ltd., Parkville, Australia; Dr W. Jiskoot, National
lnstitute of Public Health and Environmental Protection, Bilthoven, Netherlands; Mrs
S. F. Langlois, Connaught Laboratories Ltd., A Pasteur Merieux Company, Ontario,
Canada; Dr Lehmann, Behringwerke, Marburg, Germany; Dr R. M. Lequin, Organon
Teknika N.V., Turnhout, Belgium; Dr T. Matuhasi, Okinawa Memorial Institute, Tokyo,
Japan; Dr H. Mirchamsy, Razi State lnstitute of Sera and Vaccines, Teheran, Islamic
Republic of Iran; Mr W. Morges, Merck Pharmaceutical Manufacturing Division,
West Point, PA, USA; Mr J. Peetermans, SmithKline Beecham, Rixensart, Belgium;
Dr B.Terrana, Tuscan lnstitute for Serotherapy and Vaccine Production (SCLAVO),
Siena, Italy; Dr R.Thorpe, National Institute for Biological Standards and Control,
Potters Bar, Herts., England; Dr H.A.Truebenbach, Behringwerke, Marburg,
Germany; Dr J. J. Walsh, Watsonia, Victoria, Australia; Professor H. Wigzell, National
Bacteriological Laboratory, Stockholm, Sweden; Dr R. Winsnes, Norwegian Medicines
Control Authority, Oslo, Norway.
References
1. Good manufacturing practices for pharmaceutical products. In: WHO Expert
Committee on Specifications for Pharmaceutical Preparations. Thirty-second
Report. Geneva, World Health Organization, 1992 (WHO Technical Report
Series, No. 823): Annex 1.
2. Good manufacturing practices for biological products. In: WHO Expert
Committee on Biological Standardization. Forty-second Report. Geneva, World
Health Organization, 1992 (WHO Technical Report Series, No. 822), Annex 1.
3. Requirements for the Collection, Processing: and Quality Control of Blood,
Blood Components, and Plasma Derivatives (Requirements for Biological
Substances No. 27, revised 1988). in: WHO Expert Committee on Biological
Standardization. Thirty-ninth Report. Geneva, Worid Health Organization, 1989
(WHO Technical Report Series, No. 786), Annex 4.
4. General Requirements for the Sterility of Biological Substances (Requirements
for Biological Substances No.6, revised 1973). In: WHO Expert Committee on
Biological Standardization. Twenty-fifth Report. Geneva, World Health
Organization, 1973 (WHO Techn~cal Report Series, No. 530), Annex 4.
5. Requirements for Continuous Cell Lines Used for Biologicals Production
(Requirements for Biological Substances No. 37). In: WHO Expert Committee on
Biological Standardization. Thirty-sixth Report. Geneva, World Health
Organization, 1987. (WHO Technical Report Series, No. 745), Annex 3.
6. The international pharmacopoeia, 3rd ed. Vol. 1, General methods of analysis.
Geneva, World Health Organization, 1979.
7. Kirkwood TBL. Design and analysis of accelerated degradation tests for the
stability of biological standards. Ill. Principles of design. Journal of biological
standardization, 1984, 12:215-224.
8. Guidelines for national authorities on quality assurance for bioiogical products.
In: WHO Expert Committee on Biological Standardization. Forty-second Report.
Geneva, World Health Organization, 1992 (WHO Technical Report Series,
No. 822), Annex 2.
Appendix 1
Possible viral contaminants in hybridomas of
murine origin
An asterisk (*) denotes a virus capable of replicating in vitro in cells of
human and monkey origin.
1. Viruses for which there is evidence of capacity for infecting
humans or primates
Hantaan virus*
Lymphocytic choriomeningitis virus (LCMV)"
Rat rotavirus*
Reovirus type 3'"
Sendai virus (murine and human parainfluenza virus type l)*
2. Viruses for which there is no evidence of capacity for infecting
humans
Ectromelia (mousepox) virus*
K virus (Polyomavirus muris 2)
Kilham rat virus (KRV)"
Lactic dehydrogenase virus (LDH)
Minute virus of mice (MVM)
Mouse adenovirus (MAV)"
Mouse cytomegalovirus (MCMV; murid (beta) herpesvirus l)*
Mouse rotavirus (EDIM, epizootic diarrhoea of infant mice)*
Murine hepatitis virus (MHV)
Murine poliovirus (Theiler's encephalomyelitis virus, GD7)
Pneumonia virus of mice (PVM)"
Polyomavirus muris 1
Rat coronavirus @CV)
Retroviruses (murine)"
Sialodacryoadenitis virus (SDAV)
Thymic virus (murid herpesvirus 3)
Toolan virus (H-l)*
Appendix 2
Human tissues that should be considered for
immunohistochemical investigations of the
reactivity of monoclonal antibodies
Tonsil, thymus, lymph node
Bone marrow, blood cells
Lung, Liver, kidney, bladder, spleen, stomach, intestine
Pancreas, parotid, thyroid, parathyroid, adrenal, pituitary
Brain, peripheral nerve
Heart, striated muscle
Ovary, testis
Skin
The tissues tested may vary with the immunological specificity of the
antibody and its proposed use.
Appendix 3
Model certificate for the release of monoclonal
antibodies '
The following lots of monoclonal antibodies produced
by in ,4 whose numbers appear on the labels of
the final containers, meet all national requirement^,^ and comply with Part
A of the "Guidelines for assuring the quality of monoclonal antibodies for
use in human^"^ (if applicable, revised 1 9 , addenda 19-1, "Good
manufacturing practices for pharmaceutical products
n7
and "Good
manufacturing practices for biological pr~duct s". ~
Lot no. Expiry date Lot no. Expiry date
As a minimum, this certificate is based on examination of the
manufacturing protocol.
The Director of the National Control Laboratory (or Authority as
appr~priate):~
Name (typed)
Signature
Date
To be provided by the national control authority of the country where the monoclonal antibody
has been manufactured, on the request of the manufacturer.
Indicate the specificity of the monoclonal antibody.
Name of manufacturer.
Country.
If any national requirements are not met, specify which one(s) and indicate why release of the
lot(s) has nevertheless been authorized by the National Control Authority.
WHO Technical Report Series, No. 822, 1992, Annex 3.
WHO Technical Report Series, No. 823, 1992, Annex 1.
WHO Technical Report Series, No. 822, 1992, Annex 1.
Or his or her representative.
O World Health Organization
WHO Technical Report Series, No. 822, 1992
Annex 4
Requirements for antimicrobic susceptibility
tests: I. Agar diffusion tests using antimicrobic
susceptibility discs (Requirements for Biological
Substances No. 26, addendum 1991 )
As part of these Requirements (revised 19811), the Expert Committee
on Biological Standardization at its thrty-third meeting
2
adopted a revised
list of codes used to identify antimicrobials contained in susceptibility test
discs. The list of codes was again revised at subsequent meetings of the
Expert Committee
s
6
to incorporate additions, deletions and changes in
nomenclature. During the period since the last revision, further requests
have been received by the WHO Secretariat for allocation of codes for new
antimicrobial substances. The new entries that have been agreed should be
incorporated into the existing list by makmg the following further
additions to Part A, section 1.6 of the Requirements?
aspoxicillin
cefbuperazone
cefdinir
cefetecol
cefteram
ceftibuten
danofloxacin
flomoxef
habekacin
isepamicin
micronomicin
rokitamycin
temafloxacin
APX
CFB
CDR
CCL"
CEM
CTB
DFX
FLO
HAB
ISP
MCR
ROK
TMX
* This name and code replace those of "cefcatacol, CTL, which were published in the forty-first
reDort of the Committee.
' WHO Technical Report Series. No. 673, 1982, p.144.
W H O Technical Report Series, No.687, 1983: p.175.
WHO Technical Report Series, No.745, 1987, p.111.
WHO Technical Report Series, No. 771, 1988, p.211.
W H O Technical Report Series, No. 800, 1990, p.180.
WHO Technical Report Series, No. 814, 1991, p. 71.
Full list of codes allocated
In view of the Expert Committee's decision no longer to annex lists of these
codes to its reports (see pp. 6-7 of the main report), a full updated list is
given here for reference. Corrections, changes in spelling (generally to
conform with recommended INNS) and additions made since publication
of the revised list of codes in 1983' are noted in the right-hand column.
Dates refer to approval by the Expert Committee rather than publication.
Antimicrobial Code Comment
actagardin
alafosfalin
amikacin
amoxicillin
amoxicillin/clavulanic acid
amphotericin B
ampicillin
apalcillin
aspoxicillin
astromicin
avilamycin
azithromycin
azlocillin
aztreonam
bacitracin
bambermycin
bekanamycin
benzylpenicillin
betamicin
bicozamycin
brodimoprim
butoconazole
carbenicillin
carumonam
cefacetrile
cefaclor
cefadroxil
cefalexin
cefaloridine
cefalotin
cefamandole
AG
AF
AN
AMX
AMC
AB
AM
APL
APX
AST
AV1
AZM
AZ L
ATM
B
F L
B K
P
BT
BCZ
BDP
BUT
C B
CAR
CAC
CEC
CFR
CN
C D
C F
MA
19853
1991
was astromycin
19906
1985,3 was flavomycin
was betamycin
WHO Technical Report Series, No.673, 1982, p.144.
WHO Technical Report Series, No.687, 1983, p.175.
WHO Technical Report Series, No.745, 1987, p.111.
WHO Technical Report Series, No. 771, 1988, p. 211.
WHO Technical Report Series, No.800, 1990, p.180.
WHO Technical Report Series, No. 814, 1991, p. 71.
Antimicrobial
cefapirin
cefatrizine
cefazedone
cefazolin
cefbuperazone
cefdinir
cefepime
cefetamet
cefetecol (was cefcatacol)
cefetrizole
cefixime
cefmenoxime
cefmetazole
cefminox
cefodizime
cefonicid
cefoperazone
ceforanide
cefotaxime
cefotetan
cefotiam
cefoxitin
cefpimizole
cefpiramide
cefpirome
cefpodoxime
cefprozil
cefradine
cef roxad in e
cefsulodin
cefsumide
ceftazidime
cefteram
ceftibuten
ceftizoxime
ceftriaxone
cefuroxirne
cetocycline
chloramphenicol
chlortetracycline
ciclacillin
cinoxacin
clarithromycin
Code Comment
C P
CTZ
CZD
CZ
CFB
CDR
FEP
CAT
CCL
CZL
CFM
CMX
CMZ
CNX
CDZ
CID
CFP
CND
CTX
CTT
CTF
FOX
C FZ
CPM
CPO
CPD
CPR
CED
CRD
CFS
CSU
C AZ
CEbI
CTB
czx
CRO
CXM
CTO
C
C H
C I
CIN
CLR
1991
1991
1987"
1990 (approved but unpublished)
1991 (was CTL 19906)
was cefetrizol
1987"
l WHO Technical Report Series, No. 673, 1982, p.144.
WHO Technical Report Series, No.687, 1983: p.175.
WHO Technical Report Series, No.745, 1987, p.111.
WHO Technical Report Series, No. 771, 1988, p.211.
WHO Technical Report Series, No.800, 1990, p.180.
WHO Technical Report Series. No. 814, 1991, p. 71.
Antimicrobial Code Comment
clavulanic acid
clindamycin
clotrimazole
cloxacillin
colistin
danofloxacin
demeclocycline
dibekacin
dicloxacillin
doxycycline
econazole
enoxacin
epicillin
epiroprim
erythromycin
etham butol
ethionamide
fleroxacin
flomoxef
flucloxacillin
flucytosine
flumequine
fosfomycin
fosmidomycin
framycetin
furaltadone
furazolidone
fusidic acid
gentamicin
habekacin
hetacillin
imipenem
isepamicin
josamycin
C LA
CM
CTR
CX
CS
D FX
D M
DKB
DX
D 0
EC
ENX
EP
EPP
E
E B
E A
FLE
FLO
FU
FCT
UB
FOS
FMD
FY
AL
FR
FA
GM
HAB
H
IPM
ISP
JM
1991
was debecakin
was fosfidomycin
1985,3 was imipemide
1991
WHO Technical Report Series, No. 673, 1982, p.144.
WHO Technical Report Series, No.687, 1983, p.175.
WHO Technical Report Series, No.745, 1987, p.111.
WHO Technical Report Series, No. 771, 1988, p. 211.
WHO Technical Report Series, No. 800, 1990, p.180.
WHO Technical Report Series, No. 814, 1991, p. 71.
Antimicrobial Code Comment
kanamycin
kitasarnycin
latarnoxef
lincomycin
lividomycin
lomefloxacin
rnecillinam
meropenem
mesulfarnide
rnetacycline
rnethenamine
meticillin
metioprim
metioxate
rnetronidazole
mezlocillin
miconazole
micronomicin
mikarnycin
rniloxacin
minocycline
nafcillin
nalidixic acid
natamycin
neomycin
netilmicin
nifuroquine
nifurprazine
nitrofural
nitrofurantoin
nitroxoline
norfloxacin
novobiocin
nystatin
oleandomycin
ornidazole
oxacillin
oxolinic acid
oxytetracycline
K
LU 1985,3 was leucornycin
M EC
MEM 1 98g5
MES
MC
M 1985,3 was methenamine mandelate
M E
MTP
MXT
MTR
MZ
MCZ
MCR 1991
M1
MIL
MNO
NF
N A
NT
N
NET
NIF
NP
FC 1985,3 was nitrofuzone
FT
NI
NOR
NB
NY
0 L
ORN 1987':
ox
0 A
OT
' WHO Technical Report Series, No. 673, 1982: p.114.
WHO Technical Report Series, No. 687, 1983. p.175.
W H O Technical Report Series, No.745, 1987, p.111.
WHO Technical Report Series, No.771, 1988, p.211.
WHO Technical Report Series, No.800, 1990, p.180.
WHO Technical Report Series, No. 814, 1991, p. 71.
Antimicrobial Code Comment
paromomycin
pentisomicin
pentizidone
pheneticillin
phenoxymethylpenicillin
pipemidic acid
piperacillin
piridicillin
piromidic acid
plauracin
polymyxin B
primycin
pristinamycin
propicillin
propikacin
ribostamycin
rifamide
rifampicin
rifamycin
rifapentine
rokitamycin
rosoxaci n
roxithromycin
sarmoxicillin
sisomicin
spectinomycin
spiramycin
streptomycin
sulbactam
sulbactam/ampicillin
sulbenicillin
sulconazole
sulfacitine
sulfadiazine
sulfadimethoxine
sulfadimidine
sulfafurazole
sulfamazone
sulfamerazine
sulfamethizole
sulfamethoxazole
P M
PIM
PTZ
P H
PV
P I
PIP
PRC
PIR
PL
P B
PRM
PT
P R
PKA
R I
RM
RA
RF
RP
ROK
ROS
RXT
S RX
SIS
SPT
SP
S
S B
SAM
SBC
SUC
R E
S D
X
SDM
I
szo
S M
sz
SMX
was pentisomycin
was phenethicillin
WHO Technical Report Series, No. 673, 1982, p.144.
WHO Technical Report Series, No. 687, 1983, p.175.
WHO Technical Report Series, No. 745, 1987, p.111.
WHO Technical Report Series, No. 771, 1988, p. 211.
WHO Technical Report Series, No.800, 1990, p.180.
WHO Technical Report Series, No. 814, 1991, p. 71.
Antimicrobial Code Comment
sulfamethoxazole/trimethoprim SXT
sulfamethoxypyridazine
sulfametomidine
sulfametrole
sulfamonomethoxine
sulfaphenazole
sulfasuccinamide
sulfathiazole
sulfisomidine
sulfomyxin
sulfonamides
talisornycin
talmetoprim
teicoplanin
temafloxacin
temocillin
terizidone
tetracycline
tetroxoprirn
thiamphenicol
ticarcillin
ticarcillin/clavulanic acid
tilbroquinol
tiliquinol
tiodonium chloride
tioxacin
tobramycin
tosufloxaci n
trimethoprim
tylosin
vancomycin
virginiamycin
SX
MT was sulfamethomidin
S L
MO 1985,3 was sulfamethoxine
PZ
SNA
ST
D
TS 1985,3 was thiosporin
SSS
TA
TLP
TEC 19853
TMX 1991
TEM
TZ
TE
TET
TP
TIC
TCC 1 98s3
TBQ
TQ
TDC
TXC
TM
TFX 1990'
TM P
TI
WHO Technical Report Series, No. 673, 1982, p.144.
WHO Technical Report Series, No. 687, 1983, 3.175.
WHO Technical Report Series, No. 745, 1987, p.111.
WHO Technical Report Series, No. 771, 1988, p. 211.
WHO Technical Report Series, No. 800, 1990, p.180.
W H O Technical Report Series: No. 814, 1991, p. 71.
Codes listed in alphabetical order
AB AF AG AL AM AMC AMX AN APL APX AST ATM AV1 AZL AZM
B BCZ BDP BK BT BUT
C CAC CAR CAT CAZ CB CCL CD GDR CDZ CEC CED CEM CF CFB
CFM CFP CFR CFS CFZ CH Cl CID CIN CLA CLR CM CMX CMZ CN
CND CNX CP CPD CPM CPO CPR CRD CRO CS CSU CTB CTF CTO
CTR CTT CTX CTZ CX CXM CZ CZD CZL CZX
D DFX DKB DM DO DX
E EA EB EC ENX EP EPP
FA FC FCT FEP FL FLE FLO FMD FOS FOX FR FT FU FY
H HAB
I IPM ISP
L LOM LU LV
M MA MC MCR MCZ ME MEC MEM MES MI MIL MNO MO MOX MT
MTP MTR MXT MZ
N NA NB NET NF NI NIF NOR NP NT NY
OA OL ORN OT OX
P PB PH PI PIM PIP PIR PKA PL PM PR PRC PRM PT PTZ PV PZ
RA RE RF RI RM ROK ROS RP RXT
S SAM SB SBC SD SDM SIS SL SM SMX SNA SP SPT SRX SSS ST
SUC SX SXT SZ SZO
TA TBQ TCC TDC TE TEC TEM TET TFX TIC TL TLP TM TMP TMX TP
TQ TS TXC TZ
0 World Health Organization
WHO Technical Report Series, No. 822, 1992
Annex 5
Laboratories approved by WHO for the
production of yellow fever vaccine
This list supersedes Annex 10 in WHO Technical Report Series, No. 771,
1988.
Bio-Manguinhos
Oswaldo Cruz Foundation
Rio de Janeiro
Brazil
Central Research lnstitute
Kasauli
Himachal Pradesh
India
National lnstitute for Virology
Sandringham
South Africa
Pasteur lnstitute of Dakar
Dakar
Senegal
Connaught Laboratories Inc. Pasteur Merieux Sera and Vaccines
Swiftwater, PA Lyon
U SA France
CSL Limited
Parkville
Victoria
Australia
Robert Koch lnstitute
Berlin
Germany
Federal Vaccine Production The Wellcome Research Laboratories
Virology Laboratory Beckenham
Yaba Kent
Lagos England
Nigeria
lnstitute of Poliomyelitis and
Viral Encephalitides
Moscow
Russian Federation
O World Health Organization
WHO Technical Report Series, No. 822, 1992
Annex 6
Biological substances: lnternational Standards
and Reference Reagents
A list of International Biological Standards, International Biological
Reference Preparations, and International Biological Reference Reagents
is issued as a separate publication.' Copies may be obtained from
appointed sales agents for WHO publications or from: Distribution and
Sales, World Health Organization, 1211 Geneva 27, Switzerland.
The Expert Committee made the following changes to the previous list.
Additions
Antisera
Anti-poliovirus serum
Types 1, 2 and 3, human
Type 1:
25 KJ/ampoule
Type 2:
50 IU/ampoule
Type 3:
5 IU/ampoule
Second International
Standard 1991
This substance is held and distributed by the International Laboratory for Biological
Standards, National Institute for Biological Standards and Control, Potters Bar, Herts.,
EN6 3QG, England.
Antigens
Rabies vaccine 16 IU/ampoule Fifth International
Standard 1991
Rabies virus 10 IU/ampoule First International
PM-glycoprotein - Standard 1991
Rabies virus 13 5 IU/ampoule First International
PM-ribonucleoprotein Standard 1991
These substances are held and distributed by t he lnternational Laboratory for
Biological Standards, State Serum Institute, 80 Amager Boulevard, Copenhagen,
Denmark.
Biological substances: International Standards and Reference Reagents, 1990. Geneva,
World Health Organization, 1991.
Blood products
Alpha-thrombin, human 100 IU/ampoule First International
Standard 1991
This substance is held and distributed by the International Laboratory for Biological
Standards, National lnstitute for Biological Standards and Control, Potters Bar, Herts.,
EN6 3QG, England.
Endocrinological substances
Calcitonin, human 17.5 IU/ampoule Second International
Standard 1991
Calcitonin, porcine 0.8 IU/ampoule Second International
Standard 1991
Thyroxine-binding 30 IU/ampoule First International
globulin Standard 1991
Tumour necrosis factor 40 000 IU/ampoule First International
alpha, human Standard 1991
These substances are held and distributed by the lnternational Laboratory for
Biological Standards, National lnstitute for Biological Standards and Control, Potters
Bar, Herts., EN6 3QG, England.
Discontinuation
Vitamin D Bottles containing Second International
approximately 6 g Standard 1949
of a solution of
vitamin D; (INN =
colecalciferol)
in vegetable oil
(1000 IU/g)
An International Unit of Vitamin D is widely taken to be equivalent to the
activity in 25 ng of pure colecalciferol.
This substance was held and distributed by the lnterna5onal Laboratory for Biological
Standards, National lnstitute for Biological Standards and Control, Potters Bar, Herts.,
EN6 3QG, England.
O World Health Organization
WHO Technical Report Series, No. 822, 1992
Annex 7
Requirements for biological substances and
other sets of recommendations
The specification of requirements to be fulfilled by preparations of
biological substances is necessary in order to ensure that these products
are safe, reliable, and potent prophylactic or therapeutic agents.
International recommendations on requirements are intended to facilitate
the exchange of biological substances between different countries and to
provide guidance to workers responsible for the production of these
substances as well as to others who may have to decide upon appropriate
methods of assay and control.
Recommended requirements and sets of recommendations concerned
with biological substances are formulated by international groups of
experts and are published in the Technical Report Series of the World
Health Organization,' as listed here.
Requirements
1. General Requirements for Manufacturing Establishments and
Control Laboratories
Revised 1965, TRS 323 (1966)
Replaced by "Good manufacturing practices for biological
products", TRS 822 (1992) and "Guidelines for national author-
ities on quality assurance for biological products", TRS 822 (1992)
2. Requirements for Poliomyelitis Vaccine (Inactivated)
Revised 1981, TRS 673 (1987)
Addendum 1985, TRS 745 (1987)
3. Requirements for Yellow Fever Vaccine
Revised 1975, TRS 594 (1976)
Addendum 1987, TRS 771 (1988)
4. Requirements for Cholera Vaccine
Revised 1968, TRS 413 (1969)
Addendum 1973, TRS 530 (1973)
5. Requirements for Smallpox Vaccine
Adopted 1966, TRS 323 (1966)
6. General Requirements for the Sterility of Biological Substances
Revised 1973, TRS 530 (1973)
'Abbreviated here as TRS
80
7. Requirements for Poliomyelitis Vaccine, Oral
Revised 1989, TRS 800 (1990)
8.a Requirements for Diphtheria, Tetanus, Pertussis and Combined
10. Vaccines
Revised 1989, TRS 800 (1990)
9. Requirements for Procaine Benzylpenicdh in Oil with Aluminium
Monostearate
Revised 1966, TRS 361 (1967)
Discontinued 1989, TRS 800 (1990)
11. Requirements for Dried BCG Vaccine
Revised 1985, TRS 745 (1987)
Amendment 1987, TRS 77 1 (1988)
12. Requirements for Measles Vaccine (Live)
Revised 1987, TRS 771 (1988)
13. Requirements for Anthrax Spore Vaccine (Live, for Veterinary Use)
Adopted 1966, TRS 361 (1967)
14. Requirements for Human Immunoglobulin
Adopted 1966, TRS 361 (1967)
Replaced by Requirements No. 27
15. Requirements for Typhoid Vaccine
Adopted 1966, TRS 361 (1967)
16. Requirements for Tuberculins
Revised 1985, TRS 745 (1987)
17. Requirements for Influenza Vaccine (Inactivated)
Revised 1990, TRS 814 (1991)
18. Requirements for Immune Sera of Animal Origin
Adopted 1968, TRS 413 (1969)
19. Requirements for Rnderpest Cell Culture Vaccine (Live) and
Rinderpest Vaccine (Live)
Adopted 1969, TRS 444 (1979)
20. Requirements for Bn~celln n b o ~ ~ r s Strain 19 Vaccine (Live, for
Veterinary Use)
Adopted 1969, TRS 444 (1970)
Addendum 1975, TRS 594 (1976)
21. Requirements for Snake Antivenins
Adopted 1970, TRS 463 (1971)
22. Requirements for Rabies Vaccine for Human Use
Revised 1980, TRS 658 (1981)
23. Requirements for Meningococcal Polysaccharide Vaccine
Adopted 1975, TRS 594 (1976)
Addendum 1980, TRS 658 (1981)
24. Requirements for Rubella Vaccine (Live)
Adopted 1976, TRS 610 (1977)
Addendum 1980, TRS 658 (1981)
25. Requirements for Brucella melitensis Strain Rev. 1 Vaccine (Live, for
Veterinary Use)
Adopted 1976, TRS 610 (1977)
26. Requirements for Antimicrobic Susceptibility Tests
I. Agar Diffusion Tests Using Antimicrobic Susceptibility Discs
Revised 1981, TRS 673 (1982)
Addendum 1982, TRS 687 (1983)
Addendum 1985, TRS 745 (1987)
Addendum 1987, TRS 771 (1988)
Addendum 1989, TRS 800 (1990)
Addendum 1990, TRS 8 l 4 (1991)
Addendum 1991, TRS 822 (1992)
Discontinued 1991, TRS 822 (1992)
27. Requirements for the Collection, Processing, and Quality Control of
Blood, Blood Components and Plasma Derivatives
Revised 1988, TRS 786 (1989)
28. Requirements for Influenza Vaccine (Live)
Adopted 1978, TRS 638 (1979)
29. Requirements for Rabies Vaccine for Veterinary Use
Adopted 1980, TRS 658 (1981)
30. Requirements for Thromboplastins and Plasma Used to Control Oral
Anticoagulant Therapy
Revised 1982, TRS 687 (1983)
31. Requirements for Hepatitis B Vaccine Prepared from Plasma
Revised 1987, TRS 771 (1988)
32. Requirements for Rift Valley Fever Vaccine
Adopted 1981, TRS 673 (1982)
33. Requirements for Louse-Borne Human Typhus Vaccine (Live)
Adopted 1982, TRS 687 (1983)
34. Requirements for Typhoid Vaccine (Live, Attenuated, Ty 21a, Oral)
Adopted 1983, TRS 700 (1984)
35. Requirements for Rift Valley Fever Vaccine (Live, Attenuated) for
Veterinary Use
Adopted 1983, TRS 700 (1984)
36. Requirements for Varicella Vaccine (Live)
Adopted 1984, TRS 725 (1985)
37. Requirements for Continuous Cell Lines Used for Biologicals
Production
Adopted 1985, TRS 745 (1987)
38. Requirements for Mumps Vaccine (Live)
Adopted 1986, TRS 760 (1987)
39. Requirements for Hepatitis B Vaccines Made by Recombinant DNA
Techniques in Yeast
Adopted 1986, TRS 760 (1987)
Replaced by Requirements No. 45
40. Requirements for Rabies Vaccine (Inactivated) for Human Use
Produced in Continuous Cell Lines
Adopted 1986, TRS 760 (1957)
41. Requirements for Human Interferons Made by Recombinant DNA
Techniques
Adopted 1987, TRS 771 (1988)
42. Requirements for Human Interferons Prepared from Lymphoblastoid
Cells
Adopted 1988, TRS 786 (1989)
43. Requirements for Japanese Encephalitis Vaccine Qnactivated) for
Human Use
Adopted 1987, TRS 771 (1988)
45. Requirements for Hepatitis B Vaccines Made by Recombinant DNA
Techniques
Adopted 1988, TRS 786 (1989)
46. Requirements for Haemophilzis Type b Conjugate Vaccines
Adopted 1990, TRS 814 (1991)
Requirements for Immunoassay Kits [unnumbered]
Adopted 1980, TRS 658 (1981)
Other documents
Recommendations for the assessment of binding-assay systems (including
immunoassay and receptor assay systems) for human hormones and their
binding proteins (A guide to the formulat'ion of requirements for reagents
and assay kits for the above assays and notes on cytochemical bioassay
systems)
TRS 565 (1975)
Development of national assay sen~ices for hormones and other substances
in community health care
TRS 565 (1975)
Report of a WHO Working Group on the Standardization of Human
Blood Products and Related Substances
TRS 610 (1977)
Guidelines for quality assessment of antitumour antibiotics
TRS 658 (1981)
The national control of vaccines and sera
TRS 658 (1981)
Replaced by "Guidelines for national authorities on quality assurance
for biological products", TRS 822 (1992)
Procedure for approval by WHO of yellow fever vaccines in connexion
with the issue of international vaccination certificates
TRS 658 (1981)
A review of tests on virus vaccines
TRS 673 (1982)
Standardization of interferons (reports of WHO informal consultations)
TRS 687 (1983)
TRS 725 (1985)
TRS 771 (1988)
Production and testing of the WHO yellow fever virus primary seed lot
213-77 and reference batch 168-73
TRS 745 (1987)
Report of a WHO Meeting on Hepatitis B Vaccines Produced by
Recombinant DNA Techniques
TRS 760 (1987)
Procedure for evaluating the acceptability in principle of vaccines
proposed to United Nations agencies for use in immunization
programmes, revised 1988
TRS 786 (1989)
Guidelines for the preparation, characterization and establishment of
international and other standards and reference reagents for biological
substances, revised 1989
TRS 800 (1990)
Guidelines for assuring the quality of pharmaceutical and biological
products prepared by recombinant DNA technology
TRS 814 (1991)
Good manufacturing practices for biological products
TRS 822 (1992)
Guidelines for national authorities on quality assurance for biological
products
TRS 822 (1992)
Guidelines for assuring the quality of monoclonal antibodies for use in
humans
TRS 822 (1992)
Laboratories approved by WHO for the production of yellow fever
vaccine, revised 1991
TRS 822 (1992)
World Health Organization Technical Report Series
Recent repon3:
No.
778 (1989) Health guidelines for the use of wastewater in agriculture and
aquaculture
Report of a WHO Scientific Group (74 pages)
779 (1989) Health of the elderly
Report of a WHO Expert Committee (98 pages)
780 (1989) Strengthening the performance of community health v-orkers in primary
health care
Report of a WHO Study Group (46 pages)
781 (1989) New approaches to improve road safety
Report of a WHO Study Group (62 pages)
782 (1989) Monitoring and evaluation of oral health
Report of a WHO Expert Committee (69 pages)
783 (1989) Management of human resources for health
Report of a WHO Expert Committee (61 pages)
784 (1989) The use of synthetic antigens for diagnosis of infectious diseases
Report of a WHO Scientific Group (73 pages)
785 (1989) Health surveillance and management procedures for food-handling
personnel
Report of a WHO Consultation (47 pages)
786 (1989) WHO Expert Committee on Biological Standardization
Thirty-ninth report (184 pages)
787 (1989) WHO Expert Committee on Drug Dependence
Twenty-sixth report (32 pages)
788 (1989) Evaluation of certain veterinary drug residues in food
Thirty-fourth report of the Joint FAO/WHO Expert Committee on Food
Additives (66 pages)
789 (1990) Evaluation of certain food additives and contaminants
Thirty-fifth report of the Joint FAO/WHO Expert Committee on Food
Additives (48 pages)
790 (1990) WHO Expert Committee on Specifications for Pharmaceutical
Preparations
Thirty-first report (79 pages)
791 (1990) Pesticide application equipment for vector control
Twelfth report of the WHO Expert Committee on Vector Biology and Control
(58 pages)
792 (1990) Prevention in childhood and youth of adult cardiovascular diseases:
time for action
Report of a WHO Expert Committee (105 pages)
793 (1990) Control of the leishmaniases
Report of a WHO Expert Committee (l58 pages)
794 (1990) Educational imperatives for oral health personnel: change or decay?
Report of a WHO Expert Committee (43 pages)
795 (1990) Effective choices for diagnostic imaging in clinical practice
Report of a WHO Scientific Group (131 pages)
796 (1990) The use of essential drugs
Fourth report of the WHO Expert Committee (57 pages)
797 (1990) Diet, nutrition: and the prevention of chronic diseases
Report of a WHO Study Group (203 pages)
798 (1990) Chemistry and specifications of pesticides
Thirteenth report of the WHO Expert Committee on Vector Biology and
Control (77 pages)
* Prices in developing countries are 70% of those listed here.
799 (1990) Evaluation of certain veterinary drug residues in food
Thirty-sixth report of the Joint FAOIWHO Expert Committee on Food
Additives (68 pages)
800 (1990) WHO Expert Committee on Biological Standardization
Fortieth report (221 pages)
801 (1990) Coordinated health and human resources development
Report of a WHO Study Group (53 pages)
802 (1990) The role of rcsearch and information systems in decision-making for the
development of human resources for health
Report of a WHO Study Group (54 pages)
803 (1990) Systems of continuing education: priority to district health personnel
Report of a WHO Expert Committee (50 pages)
804 (1990) Cancer pain relief and palliative care
Report of a WHO Expert Committee (75 pages)
805 (1990) Practical chemotherapy of malaria
Report of a WHO Scientific Group (141 pages)
806 (1991) Evaluation of certain food additives and contaminants
Thirty-seventh report of the Joint FAO/WHO Expert Committee on Food
Additives (49 pages)
807 (1991) Environmental health in urban development
Report of a WHO Expert Committee (65 pages)
808 (1991) WHO Expert Committee on Drug Dependence
Twenty-seventh report (17 pages)
809 (1991) Community involvement in health development: challenging health
services
Report of a WHO Study Group (56 pages)
810 (1991) Management of patients with sexually transmitted discases
Report of a WHO Study Group (l03 pages)
811 (1991) Control of Chagas disease
Report of a WHO Expert Committee (95 pages)
812 (1991) Evaluation of methods for the treatment of mental disorders
Report of a WHO Scientific Group (75 pages)
813 (1991) Safe use of pesticides
Fourteenth report of the WHO Expert Committee on Vector Biology
and Control (27 pages)
814 (1991) WHO Expert Committee on Biological Standardization
Forty-first report (79 pages)
815 (1991) Evaluation of certain veterinary drug residues in food
Thirty-eighth report of the Joint FAO/WHO Expert Committee on Food
Additives (66 pages)
816 (1992) Rheumatic diseases
Report of a WHO Scientific Group (59 pages)
817 (1992) Oral contraceptives and neoplasia
Report of a WHO Scientific Group (46 pages)
818 (1992) Vector resistance to pesticides
Fifteenth report of the WHO Expert Committee on Vector Biology and Control
(62 pages)
819 (1992) The hospital in rural and urban districts
Report of a WHO Study Group on the Functions of Hospitals at the First
Referral Level (74 pages)
820 (1992) Recent advances in medically assisted conception
Report of a WHO Scientific Group (118 pages)
821 (1992) Lymphatic filariasis: the disease and its control
Fifth report of the WHO Expert Committee on Filariasis (71 pages)
,